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United States Patent |
5,198,560
|
Kadow
,   et al.
|
March 30, 1993
|
Cytotoxic bicyclo[7.3.1]tridec-4-ene-2,6-diyne compounds and process for
the preparation thereof
Abstract
The present invention relates to a novel and efficient process for the
preparation of 8-hydroxybicyclo[7.3.1]tridec-4-ene-2,6-diyne ring system
which is part of the aglycone of esperemicin and to novel cytotoxic
antitumor agents having said bicyclic ring system. The present invention
also provides a method for treating mammalian malignant tumors by
administering to an animal in need of such treatment an antitumor
effective amount of a compound of the present invention.
Inventors:
|
Kadow; John F. (Wallingford, CT);
Wittman; Mark D. (Cheshire, CT)
|
Assignee:
|
Bristol-Myers Squibb Company (New York, NY)
|
Appl. No.:
|
782942 |
Filed:
|
October 25, 1991 |
Current U.S. Class: |
556/12; 556/141; 556/142; 556/427 |
Intern'l Class: |
C07F 007/02; C07F 015/06 |
Field of Search: |
556/141,142,427,12
|
References Cited
Other References
J. Am. Chem. Soc., 1987, 109:3461 and 3462.
J. Am. Chem. Soc., 1987, 109:3464 and 3466.
Kende, et al., Tet. Lett. 1988, 29:4217-4220.
Magnus, et al., J. Am. Chem. Soc., 1988, 110:1626-1628.
Magnus, et al., J. Am. Chem. Soc., 1988, 110:6921-6923.
Tomioka, et al., Tet. Lett., 1989, 30:851-854.
Magnus, et al., Tet. Lett., 1989, 30:3637-3640.
Danishefsky, et al., J. Am. Chem. Soc., 1988, 110:6890-6891.
J. Org. Chem., 1989, 54:2781-2783.
J. Am. Chem. Soc., 1989, 111:7638-7641.
Magnus, et al., J. Org. Chem., 1990, 55(6):1709-1711.
Danishefsky, et al., J. Am. Chem. Soc., 1990, 112:3253-3255.
|
Primary Examiner: Dees; Jose G.
Assistant Examiner: Nazario; Porfirio
Attorney, Agent or Firm: Yang; Mollie M.
Parent Case Text
CROSS REFERENCE
This application is a continuation-in-part of U.S. Ser. No. 621,503, filed
Nov. 30, 1990, now abandoned which is a continuation-in-part of U.S. Ser.
No. 515,387 filed Apr. 27, 1990, now abandoned the contents thereof are
hereby incorporated by reference in their entireties.
Claims
What is claimed is:
1. A process for preparing a compound having the formula
wherein
R.sup.1 is hydroxy protecting group;
R.sup.2 is H or protected hydroxy;
R.sup.3 and R.sup.4 are independently H or protected hydroxy, or R.sup.3
and R.sup.4 taken together represent a protected keto group; and
R.sup.5 is C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, or
C.sub.6-10 aryl substituted with one or more groups selected from
C.sub.1-5 alkyl and C.sub.1-5 alkoxy, which comprises the steps of:
a) reacting a compound having the formula
##STR39##
with a compound having the formula
R.sup.5 --S--Al(R.sup.6).sub.2
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as defined
above and R.sup.6 is C.sub.1-5 alkyl; and
b) reacting the product of step a with a reagent selected from
Ti[O--(C.sub.1-5)alkyl].sub.4 and XTi[O--(C.sub.1-5)alkyl].sub.3, wherein
X is halogen.
2. A compound having the formula
##STR40##
wherein R.sup.1 is hydroxy protecting group;
R.sup.2 is H or protected hydroxy;
R.sup.3 and R.sup.4 are independently H or protected hydroxy, or R.sup.3
and R.sup.4 taken together represent a protected keto group; and
R.sup.5 is C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, or
C.sub.6-10 aryl substituted with one or more groups selected from
C.sub.1-5 alkyl and C.sub.1-5 alkoxy.
3. A compound of claim 2 wherein R.sup.2, R.sup.3, and R.sup.4 are each
hydrogen.
4. A compound of claim 2 wherein R.sup.2, R.sup.3, and R.sup.4 are each
hydrogen, R.sup.1 is trialkylsilyl, and R.sup.5 is phenyl.
5. A compound of claim 2 wherein R.sup.2, R.sup.3, and R.sup.4 are each
hydrogen, R.sup.1 is t-butyldimethylsilyl, and R.sup.5 is phenyl.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to cytotoxic compounds, their use as
antitumor agents, a novel process for their preparation, and intermediates
produced thereby.
2. Background Art
Esperamicins and calichemicins belong to a class of extremely potent
antitumor antibiotics isolated from microbial sources. Structure
elucidation studies of the esperamicins and calichemicins were reported in
J. Am. Chem. Soc., 1987, 109:3461-3462, and J. Am. Chem. Soc., 1987,
109:3464-3466, respectively. These antibiotics share a common aglycone
core which contains a bicyclo[7.3.1]tridecane ring system with an allylic
trisulfide side chain.
##STR1##
The proposed mechanism of action of these antibiotics involves, first, a
bioreductive activation of the trisulfide to generate a thiol which adds
intramolecularly to the .alpha.,.beta.-unsaturated enone. The resulting
change of hybridization of the bridgehead carbon atom brings the two ends
of the diynene portion into closer proximity to coalesce and form a
benzene 1,4-diradical which is capable of abstracting a hydrogen atom from
the sugar phosphate backbone of DNA to effect single and double stranded
breakage.
The unique structure and mechanism of action of these compounds have
engendered much interest in the synthesis of the bicyclic diynene core
fragment. A number of strategies have been devised to achieve ring closure
of a cyclohexyl compound bearing the requisite diynene fragment to form
the 10-membered ring.
Kende, et al., (Tet. Lett., 1988, 29:4217-4220) treated
3,3-(1,2-ethylenedioxy)-5-(3-hexene-1,5-diynyl)-1-cyclohexenecarboxaldehyd
e with lithium bis(trimethylsilyl)amide, followed by removal of the
ethylenedioxy ketone protecting group to provide
8-hydroxy-bicyclo[7.3.1]tridec-4,9-diene-2,6-diyn-11-one.
Magnus, et al., (J. Am. Chem. Soc., 1988, 110:1626-1628) reported the
preparation of 1-(TBSoxy)-bicyclo[7.3.1]tridec-4-ene-2,6-diyn-10-one,
dicobalt hexacarbonyl complex [TBS =t-butyldimethylsilyl]from
1,4-bis(TBSoxy)-4-(7-methoxy-3-heptene-1,5-diynyl)cyclohexene dicobalt
hexacarbonyl complex upon treatment with titanium
tetrachloride/diazabicyclo[2.2.2]octane (DABCO) at -78.degree. C.
Decomplexation of the product, however, caused the molecule to collapse
into the corresponding benzenoid compound.
Magnus, et al., (J. Am. Chem. Soc., 1988, 110:692-6923) and Tomioka, et
al., (Tet. Lett.. 1989, 30:851-854) reported the preparation of
1-(TBSoxy)bicyclo[7.3.1]tridec-4-ene-2,6-diyn-13-one (bicyclic ketone)
from 1,6-bis-(TBSoxy)-6-(7-methoxy-3-heptene-1,5-diynyl)cyclohexene
dicobalt hexacarbonyl complex upon treatment with titanium
tetrachloride/DABCO, followed by decomplexation with iodine or
trimethylamine oxide. Magnus, et al., further treated the bicyclic ketone
product with potassium hexamethyldisilazane (KHMDS) and phenylselenium
chloride to form the .alpha.-phenylselenide which, upon oxidation with
hydrogen peroxide, provided
1-(TBSoxy)-bicyclo[7.3.1]tridec-4,9-diene-2,6-diyn-13-one (bicyclic
enone). This latter product was also obtained as a minor product when the
TBS enol ether of the bicyclic ketone was oxidized with selenium dioxide
(Magnus, et al., Tet. Lett., 1989, 30:3637-3640).
Danishefsky, et al., (J. Am. Chem. Soc., 1988, 110:6890-6891) reported the
preparation of
1-(TBSoxy)-8-hydroxy-11-methoxy-bicyclo[7.3.1]tridec-4,9,11-triene-2,6-diy
ne 13-spiroethylene epoxide from
3-methoxy-5-(TBSoxy)-5-(3-hexene-1,5-diynyl)-1,6-cyclohexadienecarboxaldeh
yde 6-spiro ethylene epoxide upon treatment with base. The product was
further elaborated to provide inter alia
1,8-dihydroxybicyclo[7.3.1]tridec-4,9-diene-2,6-diyn-11,13-dione and the
corresponding 11-ethylene ketal, and 1,8
-dihydroxy-bicyclo[7.3.1]tridec-4-ene-2,6-diyn-11,13-dione. This latter
compound was shown to cleave DNA in vitro (J. Org. Chem., 1989,
54:2781-2783 and J. Am. Chem. Soc., 1989, 111:7638-7641).
Magnus, et al., (J. Org. Chem., 1990, 55(6):1709-1711) reported the
preparation of
8-hydroxy-1-TBSoxybicyclo[7.3.1]tridec-4-ene-2,6-diyn-13-one by treating
6-TBSoxy-6-(7-oxo-3-hexene-1,5-diynyl)cyclohexanone dicobalt complex with
dibutylboron triflate/DABCO to effect ring closure, followed by
N-methyl-morpholine oxide to remove the cobalt carbonyl group.
Danishefsky, et al., (J. Am. Chem. Soc., 1990, 112:3253-3255) reported the
total synthesis of dl-calicheamicinone.
The known methods for ring closure either require the use of cumbersome
precursors which are difficult to prepare, or they yield bicyclic diynenes
lacking certain key functionalities. The process of the present invention
circumvents these problems and provides a highly efficient route to
bicyclic diynenes with multiple key functionalities. Furthermore, the
present process results in the formation of a single pair of diastereomers
and allows the introduction of the 8-hydroxy group having the same
relative stereochemical configuration as the 8-hydroxy group of the
esperamicin aglycone.
SUMMARY OF THE INVENTION
The present invention provides, in one aspect, a process for closing a
10-membered ring to form an
8-hydroxy-bicyclo[7.3.1]tridec-4-ene-2,6-diyne-13-one ring system. The
process comprises the steps of: 1) reacting a dicobalt hexacarbonyl
complexed 6-protected hydroxy
6-(7-oxo-3-heptene-1,5-diynyl)-2-cyclohexenone derivative with a
nucleophilic species (Nu) capable of 1,4-conjugated addition to the enone;
and 2) treating the resultant reaction product with a titanium reagent to
effect ring closure to form the corresponding dicobalt hexacarbonyl
complexed 1-protected hydroxy
10-Nu-8-hydroxy-bicyclo[7.3.1]tridec-4-ene-2,6-diyne-13-one derivative.
The decomplexation of the compound obtained by this process is also part
of the present invention.
Another aspect of the present invention provides a process for preparing an
8-hydroxy-bicyclo[7.3.1]tridec-4,9-diene-2,6-diyne-13-one compound which
comprises oxidative elimination of the 10-Nu substituent of
10-Nu-8-hydroxy-bicyclo[7.3.1]tridec-4-ene-2,6-diyne-13-one.
Another aspect of the present invention provides
10-Nu-8-hydroxy-bicyclo[7.3.1]tridec-4-ene-2,6-diyne-13-one derivatives
and their cobalt complexes, and 1-protected
hydroxy-8-hydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyne-13-one.
Also provided by the present invention are antitumor
bicyclo[7.3.1]tridec-4-ene-2,6-diyne-13-one derivatives of formula VIIa.
##STR2##
wherein is a double bond, single bond, or an epoxy; one of R.sup.x or
R.sup.y is hydrogen and the other is hydrogen or hydroxy; or R.sup.x and
R.sup.y together is an oxo group; R.sup.w is hydrogen, --C(O)R.sup.s,
--C(O)NR.sup.t R.sup.u or --C(O)OR.sup.v ; R.sup.z and R.sup.z' are each
hydrogen, or one of R.sup.z or R.sup.z' is hydrogen, and the other is
hydroxy, --OC(O)R.sup.s, --OC(O)NR.sup.t R.sup.u or --OC(O)OR.sup.v ;
R.sup.s is hydrogen, C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10
aryl, C.sub.7-14 aralkyl, pyridyl or quinoxalyl; R.sup.t and R.sup.u are
independently hydrogen, C.sub.1-8 alkyl, amino-substituted C.sub.2-8
alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, C.sub.7-14 aralkyl, pyridyl
or quinoxalyl; R.sup.v is C.sub.1-8 alkyl, halo-substituted C.sub.1-8
alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl or C.sub.7-14 aralkyl; or a
pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The numbering of the bicyclo[7.3.1]tridec-4-ene-2,6-diyne ring system
referred to in the specification is as follows:
##STR3##
"10-Membered ring" is the ring defined by carbon atoms 1-9 and 13 of the
bicyclo[3.7.1]tridec-4-ene-2,6-diyne ring system.
Dicobalt hexacarbonyl complexed carbon-carbon triple bond is represented by
.vertline..vertline..vertline.Co.sub.2 (CO).sub.6.
This group is also referred to in the specification as "cobalt carbonyl
complex" or "cobalt complex". The dicobalt hexacarbonyl group may be used
as carbon-carbon triple bond protecting group. Cobalt complexed acetylene
is the subject of the review by Nicholas, K. M., Accounts in Chemical
Research. 1987, 20:207-214.
"TBS" is used throughout the specification as an abbreviation for
t-butyldimethylsilyl [also referred to as
(1,1-dimethylethyl)dimethylsilyl]. "Alkyl" includes straight and branched
carbon chains. "Halo" or "halogen" includes fluorine, chlorine, bromine,
and iodine. "Pharmaceutically acceptable salt" includes, where the
compound contains one or more basic nitrogen atom, acid addition salts
formed with inorganic acids such as hydrochloric acid, sulfuric acid,
phosphoric acid, nitric acid, and the like, or with organic acids, such as
acetic acid, citric acid, fumaric acid, lactic acid, tartaric acid, and
the like.
The present invention provides a process for closing a 10-membered ring to
form an 8-hydroxybicyclo[7.3.1]tridec-4-ene-2,6-diyne-13-one derivative of
formula III which comprises the steps of: 1) reacting a dicobalt
hexacarbonyl complexed 6-protected hydroxy
6-(7-oxo-3-heptene-1,5-diynyl)-2-cyclohexenone of formula I with a
nucleophilic species (Nu) capable of 1,4-conjugated addition to the enone;
and 2) treating the resultant reaction product with a titanium reagent to
provide the corresponding dicobalt hexacarbonyl complexed 1-protected
hydroxy 10-Nu-8-hydroxy-bicyclo[7.3.1]tridec-4-ene-2,6-diyne-13-one of
formula III. The nucleophilic species is generally an organometallic
reagent Nu-M wherein Nu is a nucleophilie capable of 1,4-conjugated
addition to an .alpha.,.beta.-unsaturated carbonyl compound, and M is a
monovalent metal cation or a substituted metal having valency higher than
one. This process is illustrated in Scheme I in which preferred reagents
are exemplified. It will be appreciated that although preferred reagents
are used to illustrate the invention in the following Schemes, the
invention is by no means limited thereto.
##STR4##
In scheme I, R.sup.1 is ahydroxy protecting group; R.sup.2 is hydrogen or a
protected hydroxy group; R.sup.3 and R.sup.4 are independently hydrogen or
protected hydroxy group; or R.sup.3 and R.sup.4 taken together with the
carbon atom to which they are attached represent a protected keto group.
R.sup.5 SA1(R.sup.6).sub.2 exemplifies Nu-M;R.sup.5 and R.sup.6 are
independently C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, or
C.sub.6-10 aryl substituted with one or more groups selected from
C.sub.1-5 alkyl and C.sub.1-5 alkoxy.
The choice of hydroxy protecting group and ketone protecting groups is not
particularly limited; the protecting groups may be any that can be readily
replaced with hydrogen under conditions which do not affect other
functional groups in the molecule.
Examples of hydroxy protecting group include, but are not limited to, a)
formation of ether linkage with i) lower alkyl or lower alkenyl group,
e.g., methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, and
propenyl; ii) aralkyl group, e.g., benzyl, diphenylmethyl,
triphenylmethyl, and tris(p-methoxyphenyl)methyl; and iii) triorganosilyl
group, e.g., trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,
triisopropylsilyl; b) formation of acetal or ketal with, for example,
tetrahydropyran, methoxymethyl, methoxyethoxymethyl, methylthiomethyl,
tetrahydrothiofuranyl, and tetrahydrothiopyranyl; and c) formation of
ester with i) optionally substituted lower alkanoyl, e.g., formyl, acetyl,
propionyl, butyryl, trifluoroacetyl, chloroacetyl, methoxyacetyl, and
phenoxyacetyl; ii) benzoyl or p-nitrobenzoyl; and iii) optionally
substituted alkoxycarbonyl, e.g., methoxycarbonyl, ethoxycarbonyl,
t-butyloxycarbonyl, isobutyloxycarbonyl, trichloroethoxycarbonyl, and
tribromoethoxycarbonyl. Preferred hydroxy protecting group is
t-butyldimethylsilyl.
A ketone protecting group may be one in which the oxo functionality has
been converted into a ketal group. Examples of suitable ketal groups
include, but are not limited to, a) dialkyl ketals such as dimethyl and
diethyl ketals, and 2,2,2-trichloroethyl ketal; b) cyclic ketals such as
1,3-dioxolan, 1,3-dioxan, 2,2-dimethyl-1,3-dioxan, and 4-bromomethyl-
1,3-dioxolan; c) thio ketals and hemithioketals such as 1,3-oxathiolan,
1,3-oxathian, 1,3-dithian, 1,3-dithiolan, and 2,2-di(lower
alkyl)-1,3-dithian. Preferred ketone protecting groups are cyclic ketals
such as 1,3-dioxolan and 1,3-dioxan.
In one preferred embodiment, R.sup.2 is hydrogen. In another preferred
embodiment, R.sup.3 and R.sup.4 are both hydrogen. Yet in another
preferred embodiment, R.sup.1 is a triorganosilyl group. In a more
preferred embodiment, R.sup.2, R.sup.3, and R.sup.4 are each hydrogen, and
R.sup.1 is a triorganosilyl group; most preferably, R.sup.1 is
t-butyldimethylsilyl.
According to Scheme I, a compound of formula I is treated with a
thioaluminum compound having the formula R.sup.5 S-Al(R.sup.6).sub.2,
wherein R.sup.5 and R.sup.6 are organic residues such as C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, and C.sub.6-10 aryl substituted
with one or more groups selected from alkyl and alkoxy. Preferred
thioaluminum compounds are dialkyl(phenylthio)aluminum, for example,
dimethyl(phenylthio)aluminum, i.e., (CH.sub.3).sub.2 AlSC.sub.6 H.sub.5.
It will be understood that the thioaluminum reagent is an example of an
organometallic compound, Nu-M as previously defined. In general, for Nu-M,
the metal cation M may be one commonly used to stabilize an enolate, for
example, an alkali metal, alkaline earth metal, aluminum, zinc, and the
like; preferably, the metal cation is aluminum. The nucleophilic species
Nu is one capable of 1,4-conjugated addition to an
.alpha.,.beta.-unsaturated carbonyl compound, and which may be eliminated
upon oxidation to regenerate a carbon-carbon double bond; examples of such
nucleophilic species include sulfur and selenium nucleophiles; preferably,
the nucleophilic species is a sulfur nucleophile.
The reaction is carried out in an inert aprotic organic solvent such as
tetrahydrofuran, hexane, etc., or a mixture thereof, at temperature of
below ambient temperature, suitably at 0.degree. C. or below. The reaction
generates in situ an aluminum enolate of formula II which may be directly
subjected to the ring closure reaction described infra. The reaction
mixture containing the aluminum enolate of formula II is treated with a
titanium reagent to effect intramolecular ring closure to give novel
cobalt complexed bicyclic diynene of formula III. Examples of suitable
titanium reagents include, but are not limited to, titanium alkoxides
Ti[O-(C.sub.1-5)alkyl].sub.4 and titanium alkoxide halides
XTi[O-(C.sub.1-5)alkyl].sub.3 wherein X is halogen, such as bromine,
chlorine, and iodine. Some specific examples of titanium reagents that may
be mentioned are titanium isopropoxide Ti(OCH(CH.sub.3).sub.2).sub.4,
titanium propoxide Ti(OCH.sub.2 CH.sub.2 CH.sub.3).sub.4, titanium
ethoxide Ti(OCH.sub.2 CH.sub.3).sub.4, and titanium isopropoxide chloride
Ti(OCH(CH.sub.3).sub.2).sub.3 Cl. The nucleophile R.sup.5
--S--Al(R.sup.6).sub.2 and the titanium reagent are used in at least
equimolar amount, but preferably in excess, relative to the diynene. Thus
up to about 10 equivalents of the sulfur nucleophile and up to about 80
equivalents of the titanium reagent may be employed. Preferably the sulfur
nucleophile is used in a range of about 1.5 to 10 equivalents, and the
titanium reagent in a range of about 1.5 to 80 equivalents, more
preferably about 20 to 40 equivalents, relative to the diynene.
The cobalt carbonyl group of compounds of formula III may be removed to
provide compounds of formula IV by treatment with known decomplexation
agents such as iodine, iron (III) nitrate, and a tertiary amine N-oxide,
e.g., N-methylmorpholine-N-oxide, trimethylamine-N-oxide, and the like.
The preferred reagent is iodine. The reaction is carried out in an inert
organic solvent such as benzene, dichloroethane, etc; a preferred solvent
is benzene. The reaction temperature may be any that is conducive to
product formation and may be ambient temperature. The decomplexation agent
is used at least in equimolar amount relative to the diynene but,
preferably, is used in excesss of from about 1.5 to about 10 equivalents.
##STR5##
The sulfide substituent at position 10 of the bicyclic diynene of formula
IV may be oxidized to the corresponding sulfoxide, the latter group is
then eliminated to provide the enone product of formula Va. The dicobalt
complexed bicyclic diynene of formula III may be similarly converted to
the cobalt complexed enone of formula Vb.
##STR6##
Methods for oxidation of sulfides and elimination of sulfoxides to provide
.alpha.,.beta.-unsaturated carbonyl compounds are generally well known in
the art. The sulfide substituent of compounds of formulas IV and III may
be oxidized to the corresponding sulfoxide using a variety of reagents,
including, but are not limited to, hydrogen peroxide, peracids,
periodates, perborates, acyl nitriles, and the like. The reaction is
carried out in a suitable inert organic solvent such as lower alcohol or
aqueous lower alcohol at a temperature and for a period suitable to cause
the elmination of the sulfoxide to form the .alpha.,.beta.-unsaturated
bicyclic diynene products of formulas Va and Vb, respectively. Preferably,
the reaction is carried out at room temperature, and the reaction is
usually complete in less than 10 hours to yield the desired enone product.
Compounds of formula Vb may be converted into compounds of formula Va by
decomplexation methods earlier described. It will be appreciated that,
even though sulfide substituents are exemplified, selenide substitutents
may be similarly converted to enones of formulas Va and Vb.
In one preferred embodiment of the invention, the sulfide substituent at
position 10 of compounds of formulas IV and III is phenyl sulfide, and the
oxidation/elimination reaction is carried out at room temperature with
sodium periodate as the oxidizing agent, or with m-chloroperbenzoic acid
(mCPBA) at about -78.degree. C. with subsequent warming to a temperature
sufficient to effect the elimination, e.g. ambient temperature.
Alternatively, a compound of formula III may be converted to the
corresponding compound of formula Va in one step by treating the dicobalt
hexacarbonyl complexed compound of formula III with metachloroperbenzoic
acid (mCPBA). The reaction is carried out in an inert organic solvent such
as methylene chloride at a temperature conducive to product formation,
preferably at about room temperature. The reaction is generally complete
in a few hours. mCPBA is used in at least equivalent amount to the
bicyclic diynene compound, but preferably, it is used in excess of up to
about 4 equivalents of the diynene.
In yet another method, a dicobalt hexacarbonyl complexed compound of
formula III in inert organic solvent such as methylene chloride is treated
with mCPBA at reduced temperature, e.g. at about -78.degree. C.;
optionally, an alkyne such as 1-hexyne is added to the reaction mixture,
and the reaction mixture is then allowed to warm to ambient temperature.
The resulting product is dissolved in acetone and treated with cerium
ammonium nitrate (CAN) in the presence of a tertiary amine, e.g.
triethylamine to provide the corresponding compound of formula Va.
Preferably, CAN is used in excess relative to the diynene cobalt complex,
more preferably at least 3 equivalents of CAN is used relative to the
diynene.
The present invention also provides novel compounds of formulas III and IV
which are useful as intermediates and are prepared by the processes
described above. For compounds of formula IV the R.sup.1 hydroxy
protecting group may be removed using methods well known in the art to
provide the corresponding 1-hydroxy compounds. The deprotection method
used depends on the nature of the protecting group and may be, for
example, hydrolysis under acidic or basic conditions, alcoholysis. When
R.sup.1 is t-butyldimethylsilyl, this group may be removed with, for
example, trifluoromethanesulfonic acid tetrabutylammonium fluoride, or
aqueous hydrofluoric acid in acetonitrile. In compounds of formula IV
wherein R.sup.2 is protected hydroxy, or wherein one of R.sup.3 or
R.sup.4, or both are protected hydroxy, such hydroxy protecting group may
also be removed by methods as described above for R.sup.1. In compounds of
formula IV wherein R.sup.3 and R.sup.4 together represent a protected
ketone, deprotection may be effected by conventional methods such as acid
hydrolysis.
Thus, another aspect of the invention provides a bicyclic diynene of
formula VIa.
##STR7##
wherein R.sup.a is hydrogen or a hydroxy protecting group; R.sup.b is
hydrogen, hydroxy or a protected hydroxy group, R.sup.c and R.sup.d are
independently hydrogen, hydroxy, a protected hydroxy group; or R.sup.c and
R.sup.d together are an oxo group or a protected keto group; and R.sup.a
is as defined above. A preferred embodiment provides compounds of formulas
VIa wherein R.sup.a is hydrogen or a triorganosilyl group, preferably
t-butyldimethylsilyl. Another preferred embodiment provides compounds of
formulas VIa where R.sup.b is hydrogen. Another preferred embodiment
provides compounds of formulas VIa wherein R.sup.c and R.sup.d are each
hydrogen. Another preferred embodiment provides compounds of formulas VIa
wherein R.sup.5 is as previously defined, and is preferably a C.sub.6-10
aryl or substituted aryl group, and most preferably phenyl or alkoxy
substituted phenyl. One particularly preferred embodiment provides
compounds of formula VIa wherein R.sup.a is trialkylsilyl, preferably
t-butyldimethylsilyl; R.sup.b, R.sup.c, and R.sup.d are hydrogen; and
R.sup.5 is phenyl, or alkyl or alkoxy substituted phenyl.
The present invention also provides novel compounds of formula VII wherein
R.sup.1 is a hydroxy protecting group; preferably R.sup.1 is
t-butyldimethylsilyl.
##STR8##
In yet another aspect, the present invention provides novel compounds
having the formula VIIa
##STR9##
wherein is a double bond, a single bond, or an epoxy; one of R.sup.x or
R.sup.y is hydrogen and the other is hydrogen or hydroxy; or R.sup.x and
R.sup.y together is an oxo group; R.sup.w is hydrogen, --C(O)R.sup.s,
--C(O)NR.sup.t R.sup.u or --C(O)OR.sup.v ; R.sup.z, and R.sup.z' are each
hydrogen, or one of R.sup.z or R.sup.z' is hydrogen, and the other is
hydroxy, --OC(O)R.sup.s, --OC(O)NR.sup.t R.sup.u or --OC(O)OR.sup.v ;
R.sup.s is hydrogen, C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10
aryl, C.sub.7-14 aralkyl, pyridyl or quinoxalyl; R.sup.t and R.sup.u are
independently hydrogen, C.sub.1-8 alkyl, amino-substituted C.sub.2-8
alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, C.sub.7-14 aralkyl, pyridyl
or quinoxalyl; R.sup.v is C.sub.1-8 alkyl, halo-substituted C.sub.1-8
aalkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl or C.sub.7-14 aralkyl; or a
pharmaceutically acceptable salt thereof.
One preferred embodiment provides compounds of formula VIIb
##STR10##
wherein is a double bond, a single bond, or an epoxy; one of R.sup.x or
R.sup.y is hydrogen and the other is hydrogen or hydroxy; or R.sup.x and
R.sup.y together is an oxo group; R.sup.w is hydrogen, --C(O)R.sup.s,
--C(O)NR.sup.t R.sup.u or --C(O)OR.sup.v ; R.sup.z is hydrogen, hydroxy,
--OC(O)R.sup.s, --OC(O)NR.sup.t R.sup.u or --OC(O)OR.sup.v ; R.sup.s is
hydrogen, C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl,
C.sub.7-14 aralkyl, pyridyl or quinoxalyl; R.sup.t and R.sup.u are
independently hydrogen, C.sub.1-8 alkyl, amino-substituted C.sub.2-8
alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, C.sub.7-14 aralkyl, pyridyl
or quinoxalyl; R.sup.v is C.sub.1-8 alkyl, halo-substituted C.sub.1-8
alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl or C.sub.7-14 aralkyl; or a
pharmaceutically acceptable salt thereof. More preferably, R.sup.w is
hydrogen.
Another preferred embodiment provides compounds of formula VIIb wherein is
a double bond or an epoxy, R.sup.w, R.sup.x and R.sup.y are each hydrogen,
R.sup.z is hydroxy, --OC(O)R.sup.s, --OC(O)NR.sup.t R.sup.u or
--OC(O)OR.sup.v ; R.sup.s is hydrogen, C.sub.1-8 alkyl, C.sub.3-6
cycloalkyl, C.sub.6-10 aryl, C.sub.7-14 aralkyl, pyridyl or quinoxalyl;
R.sup.t and R.sup.u are independently hydrogen, C.sub.1-8 alkyl,
amino-substituted C.sub.2-8 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl,
C.sub.7-14 aralkyl, pyridyl or quinoxalyl; R.sup.v is C.sub.1-8 alkyl,
halo-substituted C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl or
C.sub.7-14 aralkyl. More preferably, R.sup.s is C.sub.1-8 alkyl or
quinoxalyl; R.sup.t is hydrogen and R.sup.u is C.sub.1-8 alkyl,
amino-substituted C.sub.1-8 alkyl, pyridyl or quinoxalyl; or R.sup.t and
R.sup.u are each C.sub.1-8 alkyl; R.sup.v is C.sub.1-8 alkyl or
halo-substituted C.sub.1-8 alkyl.
Another preferred embodiment provides compounds of formula VIIb wherein
R.sup.w and R.sup.z are each hydrogen, is a single bond or a double bond,
one of R.sup.x or R.sup.y is hydrogen and the other is hydrogen or
hydroxy, or R.sup.x and R.sup.y together is an oxo group. In a more
preferred embodiment, R.sup.w, R.sup.x, R.sup.y and R.sup.z are each
hydrogen, is a single bond. In another preferred embodiment, R.sup.w and
R.sup.z are each hydrogen, is a double bond, one of R.sup.x or R.sup.y is
hydrogen and the other is hydrogen or hydroxy, or R.sup.x and R.sup.y
together is an oxo group.
Compounds of formula VIIb wherein R.sup.w is hydrogen; R.sup.z is hydroxy;
one of R.sup.x or R.sup.y is hydrogen and the other is hydrogen or
hydroxy; or R.sup.x and R.sup.y together is an oxo group; and is a double
bond may be obtained from corresponding compounds of formula Va in which
R.sup.2 is hydrogen upon removal of the various protecting groups using
deprotecting methods known in the art as previously discussed for
compounds of formula IV. Compounds of formula VIIb wherein R.sup.w,
R.sup.x and R.sup.y are each hydrogen, R.sup.z is hydroxy, and is a
double bond, may be converted to the corresponding compound in which one
of R.sup.x or R.sup.y is hydroxy, or R.sup.x and R.sup.y together is an
oxo group using conventional allylic oxidation reagent such as selenium
dioxide; preferably, in this process the hydroxy groups are protected with
a suitable blocking group such as t-butyldimethylsilyl, prior to
oxidation. The oxidation typically yields a mixture of the allylic alcohol
and the corresponding oxo products; this mixture may be separated by
conventional chromatography techniques. The protecting groups are removed
after the oxidation and separation to provide the desired compounds.
The compound of formula VIIb wherein R.sup.w, R.sup.x, R.sup.y and R.sup.z
are each hydrogen and is a single bond may be prepared by the procedure
depicted in Scheme II.
##STR11##
In Scheme II, R.sup.1 and R are independently a hydroxy protecting group;
R.sup.1 is preferably t-butyldimethylsilyl, R is preferably
trimethylsilyl. Compound (1) is depicted with the preferred leaving group,
phenoxy; however, other leaving groups, for example,
trifluoromethanesulfonyloxy, methoxy or acetoxy, may also be used.
Cyclization of compound (1) to compound (2) is effected by treating
compound (1) with a Lewis acid; suitable Lewis acids are for example
titanium (IV) chloride, boron triflouride etherate, ethyl aluminum
dichloride, titanium (IV) isopropoxide, and the like, or a mixture
thereof; preferred Lewis acid include ethyl aluminum dichloride, and a
mixture of titanium (IV) chloride and titanium (IV) isopropoxide. The
Lewis acid is used in at least equimolar amount relative to compound (1).
The reaction is carried out in a suitable inert organic solvent such as a
chlorinated hydrocarbon, e.g. methylene chloride, and typically at reduced
temperature, for example, between -78.degree. C. and 0.degree. C., for a
period of time sufficient to effect cyclization of the starting material,
generally the reaction is complete in one hour or less.
Dicobalt hexacarbonyl of compound (2) may be removed in a manner similar to
that previously described for compounds of formula III using a
decomplexation reagent such as ferric nitrate, trimethylamine N-oxide,
mCPBA, or CAN. Preferably, the decomplexation agent is ferric nitrate, and
the reaction is carried out in an alcohol solvent such as methanol or
ethanol at room temperature to provide compound (3). The hydroxy
protecting group of compound (3) is then removed using a conventional
deprotecting method as previously discussed to provide compound (4).
Compound (3) can be converted to a compound of formula VIIb wherein
R.sup.w, R.sup.x, R.sup.y and R.sup.z are each hydrogen and is a double
bond by the following procedure depicted in Scheme III.
##STR12##
In Scheme III, R.sup.1 is a hydroxy protecting group, preferably
t-butyldimethylsilyl. Compound (3) is treated with a base to generate the
enolate, which is reacted with 2,2'-dipyridyl disulfide to give the
9-pyridylthio-substituted intermediate, compound (4). In this step the
base may be any capable of deprotonation, examples of which include
potassium or lithium bis(trimethylsilyl)amide, lithium diisopropylamide,
and the like; the preferred base is potassium bis(trimethylsilyl)amide.
The reaction is carried out in an inert solvent such as tetrahydrofuran
and at temperature below 0.degree. C., e.g. at about -78.degree. C.
Compound (4) is oxidized to the corresponding sulfoxide using an oxidant
such as mCPBA. The reaction is carried out in an inert organic solvent
such as methylene chloride at a temperature, and for a period of
sufficient time to cause the elimination of the sulfoxide to form compound
(5); typically, at ambient temperature the elimination is substantially
complete in about half an hour. Removal of the hydroxy protecting group on
compound (5) provides compound (6). Although 2,2'-dipyridyl disulfide is
illustrated as the preferred reagent, other substrates may be used to
introduce a group functionally equivalent to the phenylthio group; such
other suitable substrates are for example phenylselenyl chloride,
aryldisulfides, and alkyl- or arysulfinyl chlorides.
Compound (5) may be converted to a compound of formula VIIb wherein R.sup.w
and R.sup.z are each hydrogen, one of R.sup.x or R.sup.y is hydroxy, or
R.sup.x and R.sup.y together is an oxo group. Thus compound (5) is treated
with selenium dioxide or another agent suitable for allylic oxidation in a
suitable inert organic solvent such as dioxane and at elevated temperature
in the range of about 50.degree. to 110.degree. C. The product obtained
typically containing a mixture of the starting material, the desired
allylic alcohol as the major product (where R.sup.x or R.sup.y is
hydroxy), and the desired dione (where R.sup.x and R.sup.y together form
an oxo group); the desired components are separated by conventional
chromatographic technique. The dione may also be prepared from the allylic
alcohol using an ordinary oxidant such as manganese dioxide. The R.sup.1
hydroxy protecting group is then removed to give the desired compounds.
The compound of formula VIIb wherein R.sup.w, R.sup.x and R.sup.y are each
hydrogen, R.sup.z is hydroxy, and is a single bond may be prepared by the
procedure shown in Scheme IV.
##STR13##
In Scheme IV, R.sup.1 is a hydroxy protecting group, preferably
t-butyldimethylsilyl. Compound (7) is treated with zinc, diethylaluminum
chloride and titanium (IV) isopropoxide in tetrahydrofuran to effect ring
closure to give compound (8). The cobalt carbonyl is removed using a
decomplexation reagent as previously described, preferably the
decomplexation agent is ferric nitrate, to give compound (9). Removal of
the hydroxy protecting group yields the desired compound (10).
A compound of formula VIIa in which R.sup.z is hydrogen and R.sup.z' is
hydroxy may be converted from its 8-epimer through the use of either of
two common epimerization strategies known by practicing organic chemists.
The preferred method, commonly known as the Mitsunobu inversion (reviewed
in O. Mitsunobu, Synthesis. 1981, p. 1), entails reacting the hydroxy
group with an aryl carboxylic acid such as benzoic acid or a substituted
benzoic acid, e.g. p-nitrobenzoic acid, in the presence of triphenyl
phosphine and a dialkylazodicarboxylate, e.g. diethyl or diisopropyl
azodicarboxylate. The resulting aryl ester is subjected to ester
hydrolysis or alcoholysis under acidic or mild basic condition to produce
the desired epimerized alcohol.
In an alternate procedure, the hydroxy group is oxidized to a ketone using
a reagent known to be useful in such transformations; for example,
reagents based on activated DMSO (reviewed in Swern and Omura,
Tetrahedron, 1978, 34:1651), the periodinanone reported in Dess and
Martin, J. Oro. Chem., 1983, 48:4155, other common oxidants such as barium
manganate, pyridinium chlorochromate, pyridinium dichromate, manganese
dioxide, or tetra-n-propyl ammonium perruthenate. The ketone thus formed
may be selectively reduced with common reducing agents such as
diisobutylaluminum hydride, sodium borohydride, other aluminum hydrides,
or substituted borane reagents to provide the desired epimerized alcohol.
In this procedure, other functional groups that may also be oxidized or
reduced by the reagents used are preferably first protected.
Compounds of formula VIIa wherein R.sup.w is an acyl group, or R.sup.z is
an acyloxy group, or R.sup.w is acyl and R.sup.z is acyloxy, are prepared
from the corresponding hydroxy compound by known acylation processes. The
term or prefix "acyl" as used herein means generically or individually the
groups --C(O)R.sup.s, --C(O)NR.sup.t R.sup.u, and --C(O)OR.sup.v. In
general, where both --OR.sup.w and R.sup.z are hydroxy, the secondary
hydroxy group, i.e. R.sup.z, is preferably acylated over the tertiary
hydroxy group, i.e. --OR.sup.w. Thus, where acylation of only the tertiary
hydroxy is desired, the secondary hydroxy is first protected with a
conventional hydroxy protecting group, preferably, an organic silyl group
such as the t-butyldimethylsilyl group which can be removed with e.g.
aqueous hydrofluoric acid after the acylation of the tertiary hydroxy
group. Where bisacylated products are desired, at least two equivalents of
the the acylating agent is used relative to the bicyclic diynene.
A R.sup.s C(O)-- group may be introduced by employing the carboxylic acid
R.sup.s CO.sub.2 H or an acylating equivalent derived therefrom, examples
of which include symmetrical or mixed acid anhydride, active esters,
active amide, and acid halide. When the carboxylic acid is used, the
reaction is preferably conducted in the presence of a condensing agent
such as dicyclohexylcarbodiimide. Acid halide, for example acid chloride,
is the preferred acylating agent and the acylation reaction is carried out
generally at room temperature in an organic solvent, e.g. pyridine,
methylene chloride, tetrahydrofuran, etc., and in the presence of an acid
scavenger, e.g. a tertiary amine such as triethylamine,
dimethylaminopyridine, etc.
A R.sup.t R.sup.u NC(O)-- group may be introduced by converting the hydroxy
group into a chloroformate using phosgene or trichloromethyl
chloroformate; this intermediate is then reacted with an appropriate amine
HNR.sup.t R.sup.u either in the presence of a base, or an excess of the
amine component may be used to neutralized the acid generated by the
condensation. Where R.sup.t is hydrogen, the hydroxy group may be
condensed with an isocyanate R.sup.u N-C.dbd.O to give the carbamate. The
reaction is carried out generally at a temperature of about 20.degree. to
about 100.degree. C. in an organic solvent, e.g. pyridine, methylene
chloride, tetrahydrofuran, benzene, toluene, etc, and optionally in the
presence of a catalytic amount of dimethylaminopyridine.
A R.sup.v OC(O)-- group may be introduced by reacting the hydroxy group
with a chloroformate R.sup.v OC(O)Cl in an organic solvent, e.g. pyridine,
methylene chloride, tetrahydrofuran, etc., at ambient temperature and in
the presence of an acid scanvenger such as a tertiary amine base, e.g.
pyridine, triethylamine, dimethylaminopyridine, and the like.
Compound of VIIa wherein is an epoxy may be prepared from the
corresponding compound wherein is a double bond by oxidation with
hydrogen peroxide or a peracid. Prior to oxidation, it is desirable to
protect any free hydroxy groups. The oxidation is preferably effected with
hydrogen peroxide in the presence of sodium hydroxide. The reaction is
carried out in an alcohol solvent such as methanol at ambient temperature.
Any hydroxy protecting groups are then removed to give the desired epoxy
product.
It will be appreciated that the various compounds produced by the novel
process of the present invention can exist as optical isomers; the
individual isomers, as well as racemic mixtures and diastereomeric
mixtures, are all contemplated as being within the scope of the invention.
Similarly, the novel process of the invention is applicable to the
individual stereoisomers, as well as racemic and diastereomeric mixtures
thereof. The stereochemical notations used in the structural formulas
depicted in the specification and claims are meant to represent the
relative orientations of the various substituents on the
bicyclo[7.3.1]tridec-4-ene-2,6-diyne ring system and are not meant to
restrict the compounds represented by these formulas to specific absolute
configurations.
PREPARATION OF STARTING MATERIALS
Turning now to the preparation of compounds of formula I which are the
starting material used in the novel process of the invention. In the
following Schemes, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 have the same
meanings as defined under formula I.
The cobalt complex diynene aldehyde of formula I may be prepared from the
corresponding non-complexed acetal as depicted in Scheme V.
##STR14##
Thus, the diynene acetal VIII is treated with dicobalt octacarbonyl at room
temperature in an inert organic solvent such as heptane or methylene
chloride. The cobalt complexed diynene acetal IX is converted into the
corresponding aldehyde of formula I upon treatment with titanium
tetrachloride and 1,4-diazabicyclo[2.2.2]octane (DABCO) at -65.degree. C.
in methylene chloride. In this Scheme, R is lower alkyl or the two R
groups join to form a cyclic acetal. It is to be understood that the order
of the two reaction steps depicted in Scheme V may be reversed; i.e.,
diynene acetal VIII may be first converted to the corresponding aldehyde
by acid hydrolysis using, e.g., trifluoroacetic acid/chloroform, followed
by complexation with dicobalt octacarbonyl to provide compound of formula
I.
The diynene acetal VIII may be constructed from a 2-cyclohexenone
derivative and a diynene acetal fragment. Several strategies may be
employed to accomplish this end, and these are illustrated in Scheme VI.
##STR15##
In Scheme VI, M' is an alkali metal, for example, lithium, sodium, or
potassium. R is a lower alkyl, or the two R groups joined to form a cyclic
acetal. Ar is phenyl or phenyl substituted with a lower alkyl or alkoxy
such as methyl, ethyl, methoxy, and ethoxy.
To elaborate on Scheme VI, the anion of the diynene acetal X is treated
with a cyclohexenone of formula XI to generate a diynene-substituted
cyclohexanone enolate of formula XIII. Or, the anion X is treated with
3-arylthio substituted 2-cyclohexenone of formula XII to yield a
diynene-substituted cyclohexanone of formula XIV. Compounds of formulas
XIII and XIV are further elaborated in order to obtain the desired
cyclohexenone diynene acetal of formula VIII.
In one process of Scheme VI, the anion of the diynene acetal is treated
with a 3-arylthio substituted 2-cyclohexenone XII at reduced temperature,
e.g., at -78.degree. C., followed by warming to room temperature. The
resultant addition product XIV is then oxidized to sulfoxide using a
conventional oxidizing agent, such as mCPBA or sodium periodate, and the
reaction is preferably carried out with mCPBA at low temperature, e.g.,
-78.degree. C. Heating the sulfoxide, e.g., refluxing in carbon
tetrachloride or heating in pyridine at about 100.degree. C.-110.degree.
C. generates the cyclohexenone diynene acetal of formula VIII. As a
variation of this sequence, the sulfoxide of compound XII may be used in
place of XII to yield the sulfoxide of compound XIV. The sulfoxide of XIV
is then heated in an organic solvent, such as in refluxing heptyne or
pyridine, and optionally in the presence of a reagent for trapping the
sulfur elimination product, e.g., 2-mercaptobenzothiazole, to give
compound of formula VIII.
In the second process of Scheme VI, the anion of the diynene acetal is
treated with a cyclohexenone of formula XI in an inert solvent, such as
tetrahydrofuran, initially at low temperature, e.g., from about
-78.degree. C. to about -50.degree. C., then the reaction mixture is
allowed to warm to ambient temperature to generate the metal enolate XIII
which can be trapped and oxidized to the cyclohexenone diynene acetal of
formula VIII. In one method, the metal enolate XIII is quenched with water
at room temperature, and the resultant ketone is treated with
t-butyldimethylsilyl trifluoromethanesulfonate (TBS triflate) and
triethylamine at room temperature to provide the corresponding silyl enol
ether. The silyl enol ether may also be obtained by treating the metal
enolate XIII with TBS triflate at -78.degree. C. The silyl enol ether is
then oxidized using selenium dioxide at elevated temperature, e.g.,
refluxing temperature of the reaction mixture to provide the enone of
formula VIII. Enone of formula VIII can also be prepared by treating the
metal enolate XIII with phenylselenium chloride at -78.degree. C.,
followed by oxidizing the resultant .alpha.-phenylselenide with hydrogen
peroxide.
As depicted in Scheme VI, the metal enolate XIII may also be treated with
ArSSO.sub.2 Ar to yield a compound of formula XIV which is converted into
a compound of formula VIII as previously described. The enolate XIII may
also react with dipyridyl disulfide to give the pyridylthio analog of XIV,
which can also be similarly converted to VIII.
In yet another method for converting enolate XIII to enone of formula VIII,
the ketone obtained from quenching XIII with water is treated with a base,
e.g. LiHMDS and the enolate thus generated is reacted with ally
chloroformate to provide the corresponding enol allyl carbonate. The
reaction is carried out in an inert organic solvent such as
tetrahydrofuran initially at low temperature, e.g. at about -78.degree.
C., and then the reaction is allowed to warm to a temperature tending to
favor O-acylation over C-acylation, generally in the range of about
-10.degree. C. to about 25.degree. C. The enol allyl carbonate is
converted to compound of formula VIII with a catalytic amount of palladium
diacetate refluxing in acetonitrile.
Compound of formula (1) may be prepared in an analogous manner by reacting
the phenoxy (in place of the two -OR groups) analog of compound X with
cyclohexenone XI in THF at about 0.degree. C., and then trapping the enol
with a silyl chloride, e.g. trimethylsilyl chloride to give the silyl enol
ether. Treatment of the silyl enol ether with dicobalt octacarbonyl
provides compound (1). The phenoxy diynene starting material may be
prepared by the method provided infra for the synthesis of compound of
formula (X) substituting 3,3-diethoxypropyne with phenoxypropyne.
Compound (7) may also be prepared analogously. Thus
2-TBSoxy-2-cyclohexenone is reacted with bromine in methylene chloride and
in the presence of triethylamine to provide
3-bromo-2-TBSoxy-2-cyclohexenone. This compounds is treated with a diynene
acetal of formula X, dicobalt octacarbonyl, and then titanium
tetrachloride/DABCO under conditions given above to provide compound (7).
The diynene acetal X may be synthesized using the following procedure.
Cis-1,2-dichloroethylene is reacted with 3,3-diethoxypropyne in the
presence of copper iodide, palladium tetrakis(triphenylphosphine) and
n-butylamine, at room temperature and in the absence of light. The
product, (Z)-5-chloro-1,1-diethoxy-4-pentene-2-yne is treated with
trimethylsilylacetylene in the presence of copper iodide, palladium
tetrakis(triphenylphosphine), and n-butylamine at room temperature and
away from light to provide
(Z)-7,7-diethoxy-1-trimethylsilyl-3-hepten-1,5-diyne. The corresponding
anion is then generated by treatment with an alkali metal hydroxide, such
as lithium hydroxide.
Cyclohexenones of formulas XI and XII may be prepared from commercially
available starting materials. For example, 2-TBSoxy-2-cyclohexenone (XI,
R.sup.1 =TBS, R.sup.2 =R.sup.3 =R.sup.4 =H) may be obtained from
1,2-cyclohexandione upon treatment with a base, such as triethylamine,
imidazole or lithium diisopropylamide (LDA), followed by TBS triflate or
TBS chloride. 3-(4-Methylphenyl)-2-TBSoxy-2-cyclohexenone (XII, R.sup.1
=TBS, R.sup.2 =R.sup.3 =R.sup.4 H, Ar=4-methylphenyl) can be prepared from
1,2-cyclohexanedione upon treatment with a base such as lithium
bis(timethylsilyl)amide, followed by 4-methylphenyl
4-methylbenezenethiosulfonate; the resulting product is treated with a
base, e.g. triethylamine or imidazole, and TBS triflate or TBS chloride to
yield the desired product.
Compounds of formula XI, wherein R.sup.3 and R.sup.4 are not both H, can be
prepared from 1,4-cyclohexanedione. Thus, 1,4-cyclohexanedione is first
converted into a mono-protected form (XVa) wherein R.sup.3',R.sup.4',
together with the carbon atom they are attached, represent a protected
ketone group.
##STR16##
Preferably, the ketone is protected by conversion to a ketal. Monoketal of
formula XV may be obtained upon treatment with a controlled amount of an
alcohol, such as methanol, an orthoester, such as methyl orthoformate, a
ketal, such as 2,2-dimethoxypropane, or a diol, such as ethylene glycol.
Some 1,4-cyclohexanedione monoketals are available commercially, e.g.,
mono-ethylene ketal and mono-2,2-dimethyltrimethylene ketal.
Mono-protected 1,4-cyclohexanedione (XVa) may be converted to 4-protected
hydroxy cyclohexanone by first reducing the ketone to a hydroxy group
using, e.g., sodium borohydride. The hydroxy group may be protected using
known methods and reagents, e.g., by treating with a base such as sodium
hydride and benzyl bromide. The ketone protecting group is then removed to
provide 4-protected hydroxy cyclohexanone
##STR17##
wherein one of R.sup.3" and R.sup.4" is hydrogen and the other is a
protected hydroxy.
Compounds of formulas XVa and XVb are further elaborated to provide
compounds of formula XI, wherein R.sup.3 and R.sup.4 are not both H. One
such reaction sequence is illustrated in Scheme VII.
##STR18##
In Scheme VII, R.sup.3 and R.sup.4 are not both hydrogen but are otherwise
as defined under formula I. Cyclohexanone XV, prepared according to
procedures described above, is treated first with a base, such as lithium
diisopropylamide (LDA), and then with benzenesulfonothioic acid, S-phenyl
ester to generate the corresponding .alpha.-phenylsulfide compound XVI. A
compound of formula XVI is oxidized with lead tetraacetate to provide
.alpha.-acetoxy-.alpha.-phenylthiocyclohexanone derivative of formula
XVII, which may be converted to a corresponding silyl enol ether of
formula XVIII by first treating with a strong base, such as LDA, followed
with a silylating agent R.sup.1 -L, wherein R.sup.1 is a triorganosilyl
group and L is a leaving group. R.sup.1 -L may be, for example, TBS
triflate and iodotrimethylsilane. The silyl enol ether of formula XVIII is
converted to the corresponding 2-silyloxy-2-cyclohexenone derivative of
formula XIX upon base-catalyzed hydrolysis.
Cyclohexenones of formulas XI and XII in which R.sup.2 is hydrogen may be
converted into their corresponding .alpha.-hydroxy derivatives (R.sup.2
.dbd.OH) by treating the cyclohexenone with a base such as lithium
bis(trimethylsilyl)amide, followed by an hydroxylating agent such as the
reagent known as MoOPh (Aldrich). The .alpha.-hydroxy group may then be
protected using conventional protecting groups to provide cyclohexenones
of formulas XI and XII in which R.sup.2 represents protected hydroxy.
Compounds of formula I may also be prepared from a 7-protected
hydroxy-3-heptene-1,5-diyne and an arylsulfocyclohexenone as depicted in
Scheme VIII,
##STR19##
In Scheme VIII, M', R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Ar have the same
meaning as previously defined; P is a hydroxy protecting group. The
hydroxy protecting group is not particularly limited, the preferred one
being tetrahydropyranyl group. Protected diynene alcohol XX may be
prepared from cis-1,2-dichloroethylene and protected propargyl alcohol in
a manner similar to that described supra for the preparation of diynene
acetal X. The arylsufocyclohexenone XXI is obtained from the corresponding
arylthiocyclohexenone XII upon oxidation with mCPBA.
The condensation of the protected diynene alcohol XX and the
arylsulfocyclohexenone XXI is carried out in an inert organic solvent such
as tetrahydrofuran at an initial temperature of -78.degree. C. The
reaction temperature is allowed to gradually rise to ambient temperature
and the reaction is generally completed in a few hours. The product XXII
thus obtained is heated in pyridine at about 105.degree. C. to cause the
elimination of the aryl sulfoxide thus generating the corresponding enone.
Deprotection of the hydroxyl group may be accomplished using conventional
techniques known in the art; for example, the tetrahydropyranyl group may
be removed by acid hydrolysis. The free alcohol of formula XXIII is then
converted to the corresponding cobalt complexed diynene aldehyde of
formula I by treatment with dicobalt octacarbonyl and oxidation with
t-butoxy magnesium bromide and (azodicarbonyl)dipiperdine.
The present invention provides an efficient method for constructing an
8-hydroxybicyclo[7.3.1]tridec-4-ene-2,6-diyne-13-one ring system. The
products that may be obtained by this process, e.g., compounds of formulas
IV, Va and Vb may be further elaborated to provide the
esperamicin/calichemicin aglycone. Thus, compounds of formulas IV, Va and
Vb are useful intermediates in the synthesis of antitumor compounds
belonging to the esperamicin/calichemicin structure class. In addition,
compounds of formulas Va and Vb may be coupled to known antitumor agents,
e.g., chlorambucil may be linked to the 8-hydroxy group using an acylating
equivalent thereof, such as the acid chloride, to yield active hybrid
molecules having more desirable biological activity profile than the
parent compound.
Compounds of formula VIIa are cytotoxic compounds and are, therefore,
useful in inhibiting unwanted rapid proliferation of cells, such as that
in the neoplastic process. As therapeutic agents for treating mammalian
tumors sensitive to a compound of formula VIIa, these compounds may be
administered in the same manners as those suitable for esperamicin and
calichemicin. Thus, they may be administered by systemic or topical
routes; parenteral administration is the preferred route. The dosage may
be similar to that used for esperamicin; but in general, because compounds
of the present invention are less cytotoxic than esperamicin, dosage ten
to one thousand times that for esperamicin may be tolerated and may be
more suitable. The route of administration and the optimal dosage may be
readily ascertained by those skilled in the art and will, of course, vary
depending on factors such as the type and site of tumor to be treated, and
individual patient characteristics, such as extent of the disease, age,
weight, and the like.
The invention includes within its scope pharmaceutical compositions
containing an effective tumor-inhibiting amount of a compound of formula
VIIa in combination with an inert pharmaceutically acceptable carrier of
diluent. Such compositions may be made up in any pharmaceutical form
appropriate for the desired route of administration. Examples of such
compositions include solid compositions for oral administration such as
tablets, capsules, pills, powders and granules; liquid compositions for
oral administration such as solutions, suspensions, syrups or elixirs; and
preparations for parenteral administration such as sterile solutions,
suspensions or emulsions. The pharmaceutical compositions may also be
manufactured in the form of sterile solid compositions which can be
dissolved in sterile water, physiological saline or some other sterile
injectable medium immediately before use.
Furthermore, compounds of formula VIIa are effective in causing damages to
DNA and in double stranded DNA cleavage. They are, therefore, valuable as
laboratory reagents for such purposes.
Biological Activity
Compound of Example 4 was evaluated in vitro against three human colon
tumor cell lines: HCT-116, HCT/VM46, and HCT/VP35; the latter two are
resistant to teniposide and etoposide, respectively. The in vitro
cytotoxicity assay involved growing tumor cells on microtitre plates
employing established tissue culture methods. The concentration of the
test compound required to inhibit cell growth by 50% (IC.sub.50) was then
determined by four-fold serial dilution technique. In the experiment,
etoposide and teniposide were included as positive controls. The results
obtained are shown in Table I:
TABLE I
______________________________________
Results of In Vitro Cytotoxicity Assay
IC.sub.50 (.mu.g/ml)
Compound HCT-116 HCT-VM46 HCT/VP35
______________________________________
Example 4 0.037 <0.031 0.042
0.043 <0.031 0.046
<0.031 0.047 0.072
Etoposide 0.101 4.24 5.14
0.128 3.57 6.29
0.140 2.08 6.75
Teniposide
0.077 0.313 0.084
0.088 0.237 0.091
0.083 0.236 0.111
______________________________________
The compound of Example 4 was also evaluated against transplantable murine
P388 leukemia. CDF.sub.1 mice were implanted intraperitoneally with a
tumor inoculum of 10.sup.6 cells of P388 leukemia and treated with various
doses of the test compound. Six mice were used for each dose level and 10
mice were treated with saline to serve as control. The test compound was
administered intraperitoneally on 5 consecutive days starting on day 1
after tumor implantation. Antitumor activity is expressed as % T/C. which
is the ratio of mean survival time (MST) for the drug-treated group to the
MST of saline-treated control group.
A compound showing a % T/C. of 125 or greater is considered to have
significant antitumor activity. The results of P388 test on day 39 of the
experiment for compound of Example 4 are provided in Table II. The data
indicates this compound as having high activity against P388 leukemia.
TABLE II
______________________________________
In Vivo Activity Against P388 Leukemia
Med. Survival Survival
Dose (mg/kg/dose)
Time (d) % T/C d.5 (39)*
______________________________________
32 7 64 6/6
16 9.5 86 6/6
8 >39 >355 6/6 (4)
4 20.0 182 6/6
2 16.5 150 6/6
1 13 118 6/6
Control 11 100 10/10
______________________________________
*The number in parenthesis represents the number of surviving mice on day
39.
Compounds of Examples 6, 8 and 15 were evaluated against P388 leukemia
using the same protocol given above. Compound of Example 6 showed a
maximum %T/C. of at a dose of 20 mg/kg/dose (with one mouse surviving on
day 31); compound of Example 8 showed a max. %T/C. of at a dose of 15
mg/kg/dose; and compound of Example showed a max. %T/C. of 230 at a dose
of 40 mg/kg/dose.
SPECIFIC EMBODIMENTS
Preparation of Starting Materials
The structures of the compounds described in this section are provided on
separate pages following the Examples section.
Preparation I. (Z)-7,7-diethoxy-1-trimethylsilyl-3-hepten-1,5-diyne
[compound A]
(a) (Z)-5-chloro-1,1-diethoxy-4-pentene-2-yne [compound B]
Neat cis-1,2-dichloroethylene (4.5 ml, 60 mmol) followed by butylamine (8.0
ml, 81 mmol) was added to a solution of copper iodide (0.90 g, 4.73 mmol)
and palladium tetrakis(triphenylphosphine) (1 g, 0.86 mmol) in 40 mL of
dry benzene stirring at 25.degree. C. under argon. Immediately thereafter,
a solution of 3,3-diethoxy-propyne (5 g, 39 mmol) in 10 mL of benzene was
added via cannula. The reaction vessel was wrapped in foil to shield it
from light, and the reaction mixture was stirred for 4.2 h at 25.degree.
C. The dark brown reaction mixture was filtered by suction through a
coarse frit and diluted to approximately 180 ml with diethylether. The
solution was washed with 75 mL of water and 120 mL saturated brine, and
the organic layer was dried over anhydrous Na.sub.2 SO.sub.4 and then
concentrated in vacuo. The residue was flash chromatographed in SiO.sub.2
using 5%, then 10%, and then 15% diethyolether/pentane as eluent to
provide the desired product as clear liquid (3.9 g, 55%).
.sup.1 H NMR (CDCl.sub.3) .delta.: 6.46 (d, J=7.5 Hz, 1H), 5.92 (dd, J=1.5,
7.6 Hz, 1H), 5.45 (d, J=1.4 Hz, 1H), 3.80 (m, 2H), 3.64 (m, 2H), 1.26 (t,
J=7.0 Hz, 3H).
(b) (Z)-7,7-diethoxy-1-trimethylsilyl-3-heptene-1,5-diyne
A solution of 5-chloro-1,1-diethoxy-4-pentene-2-yne (compound B, 3.8 g, 20
mmol) in 10 mL of benzene was added via cannula to a solution of palladium
tetrakis(triphenyl-phosphine) (1.1 g, 0.95 mmol) and copper iodide (0.47
g, 2.46 mmol) in 20 mL benzene stirring at 25.degree. C. under argon.
Immediately thereafter, butylamine (4 mL, 40 mmol), followed by
trimethylsilylacetylene (5 mL, 40 mmol) was added via syringe. The
reaction vessel was wrapped in foil, and the reaction mixture was stirred
at 25.degree. C. for 4.25 h. The reaction mixture was poured into 100 mL
water and 100 mL diethyl ether and extracted. The aqueous layer was
reextracted with 2.times.40 mL of diethyl ether. The combined organic
extracts were washed with 50 mL saturated aqueous NaCl, dried over
Na.sub.2 SO.sub.4, and concentrated in vacuo. Flash chromatography over
SiO.sub.2 using 2%, then 4%, and then 5 % diethylether/pentane as eluent
provided the title compound (2.7 g, 54%) as a light brown oil.
.sup.1 H NMR (CDCl.sub.3) .delta.: 5.89 (s, 2H), 5.46 (s, 1H), 3.83-3.75
(m, 2H), 3.69-3.61 (m, 2H), 1.25 (t, J=7.1 Hz, 6H), 1.40E-4 (s, 9H).
.sup.13 C NMR (CDCl.sub.3) .delta.: 130.6, 111.6, 92.8, 92.0, 79.4, 61.3,
15.2.
Preparation II.
(Z)-6[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(7.7-diethoxy-3-heptene-1,5
-diynyl)-2-cyclohexenone [compound C]
(a)
(Z)-6-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(7,7-diethoxy-3-heptene-1,
5-diynyl)cyclohexanone [compound D]
Solid lithium hydroxide monohydrate (3 g, 71.5 mmol) was added to a
solution of (Z)-7,7-diethoxy-1-trimethylsilyl-3-heptene-1,5-diyne
(compound A, 3.20 g, 12.6 mmol) in 30 mL of tetrahydrofuran and 5 mL
water. The reaction mixture was stirred for 4 h and poured into 100 mL of
pentane and 50 mL of H.sub.2 O. The organic layer was washed with 50 mL
saturated aqueous NaCl, dried over Na.sub.2 SO.sub.4, and then
concentrated in vacuo by rotary evaporation. Methylene chloride (50 mL)
was added, and the solution was again concentrated by rotary evaporation
and then placed under high vaccuum for 25 min to provide approximately 3.3
g of a light brown oil which was immediately dissolved in 160 mL of dry
tetrahydrofuran. The solution was cooled to -78.degree. C., and then
lithium hexamethyl-disilazane (1.0M, in tetrahydrofuran, 15.5 mL, 15.5
mmol) was added via syringe in one portion. The reaction mixture was
stirred for 20 min, and then a solution of
2-tertbutyldimethylsilyloxy-2-cyclohexenone (3.65 g, 6.12 mmol) in 10 mL
of dry tetrahydrofuran, which had been precooled to approximately
-50.degree. C., was added in one portion via syringe. The reaction mixture
was stirred for 1 min, and then all of the cooling baths were removed. The
reaction mixture was allowed to stir for 2.5 h and attain ambient
temperature (25.degree. C.) to generate in situ the lithium enolate. The
enolate was quenched with water to provide the corresponding ketone as
follows. The reaction mixture was poured into 400 mL of 9:1 ethyl
acetate/diethyl-ether and 100 mL of water. The mixture was extracted, and
then the aqueous layer was reextracted with 100 ml of 1:1 ethyl
acetate/diethyl ether. The combined organic extracts were washed with 50
mL saturated aqueous NaCl, dried over anhydrous Na.sub.2 SO.sub.4, and
concentrated in vacuo. Flash chromatography using 3% then 4%, and then 5%
ethyl acetate/hexane provided 3.50 g (72%) of the desired title
cyclohexanone as a very faint green oil.
.sup.1 H NMR (CDCl.sub.3) .delta.: 5.92 (s, 2H), 5.41 (s, 1H), 3.80-3.70
(m, 2H), 3.65-3.55 (m, 2H), 2.88 (dt, J=13.3, 5.7 Hz, 1H), 2.46 (td,
J=7.7, 12.2 Hz, 1H), 2.27-2.23 (m, 1H), 2.00-1.58 (m, 5H), 1.24 (t, J=7.08
Hz, 6H), 0.91 (s, 9H), 0.046 (s, 3H), 0.018 (s, 3H).
(b)
(Z)-1,6-bis[[[(1,1-dimethylethyl)dimethyl]-silyl]oxy]-6-(7,7-diethoxy-3-he
ptene-1,5-diynyl]cyclohexene [compound E]
Neat tert-butyldimethylysilyl trifluoromethanesulfonate (0.62 mL) was added
via syringe to a solution of triethyl-amine (0.69 mL, 2.72 mmol) and
compound D prepared above (0.54 g, 1.33 mmol) in 20 ml of methylene
chloride stirring at 25.degree. C. under a nitrogen atmosphere. The
reaction mixture was stirred for 22.5 h and then poured into 100 mL of
methylene chloride and 50 mL of water. The organic layer was dried over
anhydrous Na.sub.2 SO.sub.4 and concentrated in vacuo, and the residue was
flash chromatographed on SiO.sub.2 using 3% ethyl acetate/hexane to
provide the title bis-silyloxy cyclohexene (683 mg, 98%) as a clear
liquid.
IR (NaCl, Film): 3046, 2954, 2932, 2890, 2858, 2212, 1660, 1468, 1252
cm.sup.-1.
.sup.1 H NMR (CDCl.sub.3) .delta.: 5.88 (d, J =11.0 Hz, 1H), 5.81 (dd,
J=11.0, 1.3 Hz, 1H), 4.82 (t, J=3.9 Hz, 1H), 3.79-3.74 (m, 2H), 3.64-3.58
(m, 2H), 2.05-1.99 (m, 4H), 1.81-1.56 (m, 2H), 1.24 (t, J=7.1 Hz, 6H),
0.94 (s, 9H), 0.87 (s, 9H), 0.21 (s, 3H), 0.18 (s, 3H), 0.17 (s, 3H), 0.16
(s, 3H).
.sup.13 C NMR (CDCl.sub.3) 151.1, 121.4, 118.1, 105.0, 102.1, 92.2, 91.5,
82.9, 81.5, 70.2, 61.2, 41.1, 26.1, 24.4, 18.8, 18.5, 18.4, 15.3, -2.8,
-3.0, -4.3, -4.4.
(c)
(Z)-6-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(7,7-diethoxy-3-heptene-1,
5-diynyl]-2-cyclohexenone [compound C]
Selenium dioxide (600 mg, 5.41 mmol) was added to a solution of compound E
(1.0 g, 1.98 mmol) in 60 mL of dioxane. The reaction mixture was refluxed
for 1.5 h, an additional 300 mg (2.71 mmol) of selenium dioxide was added,
and reflux continued for an additional 3 h. The reaction mixture was then
poured into 150 mL of ethyl acetate and 100 mL of saturated aqueous
NaHCO.sub.3. The aqueous layer was reextracted with 50 mL of ethyl
acetate. The combined organic layers were dried over anhydrous Na.sub.2
SO.sub.4, concentrated in vacuo, and purified by flash chromatography on
SiO.sub.2 using 3% and then 5% ethyl acetate/hexane to provide the title
cyclohexenone (620 mg, 77%) as a clear oil.
Anal. calcd. for C.sub.23 H.sub.34 O.sub.4 Si: C, 68.62; H, 8.51. Found: C,
68.26; H, 8.42.
.sup.1 H NMR (CDCl.sub.3) .delta.: 6.93-6.88(m, 1H), 5.98 (doublet of
multiplets, J=9.49 Hz, 1H), 5.89 (s, 2H), 5.41 (s, 1H), 3.80-3.70 (m, 2H),
3.66-3.55 (m, 2H), 2.82-2.66 (m, 1H), 2.53-2.40 (m, 1H), 2.35-2.16 (m,
2H), 1.24 (t, J=7.04 Hz, 6H), 0.89 (s, 9H), 0.22 (s, 3H), 0.20 (s, 3H).
.sup.13 C. NMR (CDCl.sub.3) .delta.: 194.4, 150.7, 127.4, 120.5, 120.0,
95.4, 92.4, 92.2, 84.6, 82.5, 73.6, 61.3, 39.0, 26.0, 25.4, 18.5, 15.3,
-3.0, -3.1.
Preparation III. Cobalt, hexacarbonyl
[.mu.-[6-(5,6-.eta.:5,6-.eta.)-7,7-diethoxy-3-heotene-1,5-diynyl]-6-(1,1-d
imethylethyl)-dimethylsily]oxy]-2-cyclohexenone]], di(Co-Co), (Z) [compound
F]
Solid dicobalt octacarbonyl (0.542 g, 1.58 mmol) was added to a solution of
compound C. (0.64 g, 1.584 mmol) stirring at 25.degree. C. under a
nitrogen atmosphere in 28 mL of anhydrous heptane. The reaction mixture
was stirred for 2 h and concentrated in vacuo. Flash chromatography using
2%, then 3%, and then 5% ethyl acetate/hexane on SiO.sub.2 provided 728 mg
(66%) of the desired title cobalt complex as a dark purple oil.
Anal. calcd. for C.sub.29 H.sub.34 O.sub.10 SiCo.sub.2 : C, 50.59; H, 4.98;
N, 0.0. Found: C, 50.56; H, 4.99; N, 0.0.
IR (NaCl, Film): 2978, 2956, 2932, 2896, 2858, 2094, 2056, 2028, 1700,
1624, 840 cm.sup.-1.
.sup.1 H NMR (CDCl3) .delta.: 6.89 and 6.86 (t, 3.91 Hz, 0.5H), 6.78 (d,
J=11.1 Hz, 1H), 5.99 and 5.96 (t, J=2.0 Hz, 0.5H), 5.87 (d, J =11.1 Hz,
1H), 5.58 s, 1H), 3.83-3.75 (m, 2H), 3.68-3.59 (m, 2H), 2.50-2.43 (m, 2H),
2.26 (t, 5.6 Hz, 2H), 1.2 (t, J=6.9 Hz, 6H), 0.84 (s, 9H), 0.17 (s, 3H),
0.07 (s, 3H).
.sup.13 C NMR (CDCl.sub.3) .delta.: 199.1 (b), 192.6, 149.9, 137.1, 126.9,
110.5, 101.6, 98.9, 96.0, 85.3, 82.0, 73.6, 63.2, 38.2, 25.7, 24.2, 18.3,
15.0, -3.3, -3.5.
Preparation IV. Cobalt, hexacarbonyl
[.mu.-[6-[(5,6-.eta.:5,6-.eta.)-7-oxo-3-heotene-1.5-diynyl]-6-[[1,1-dimeth
ylethyl)dimethylsiyl]oxy]-2-cyclohexenone]]di-(Co-Co), (Z) [compound G]
Titanium tetrachloride (0.195 mL, 1.79 mmol) was added via syringe to a
solution of the cobalt complexed cyclohexenone compound F (0.41 g, 0.60
mmol) and 1,4-diazabicyclo[2.2.2]octane (67 mg, 0.60 mmol) in 40 mL of
methylene chloride stirring at -65.degree. C. under a nitrogen atmosphere.
The reaction mixture was stirred for 5 min and then poured into 60 mL of
methylene chloride and 25 mL of water. The mixture was extracted, and then
the aqueous layer was reextracted with 10 mL methylene chloride. The
combined organic layers were dried over Na.sub.2 SO.sub.4, filtered,
concentrated by rotary evaporation, and chromatographed to provide the
title cobalt complexed aldehyde 301 mg, 82%) as a thick viscous reddish
purple semi solid.
Anal. calcd. for C.sub.25 H.sub.24 O.sub.9 SiCo.sub.2 : C, 48.87; H, 3.94;
N, 0.00. Found: C, 48.42; H, 3.82; N, 0.04.
.sup.1 H NMR (CDCl.sub.3) .delta.: 10.39 (s, 1H), 6.93 (dt, J=10.1, 4.0 Hz,
1H), 6.82 (d, J=10.6 Hz, 1H), 6.03 (dt, 10.1, 1.9 Hz, 1H), 5.93 (d, J=10.8
Hz, 1H), 2.56-2.18 (m, 4H), 0.87 (s, 9H), 0.19 (s, 3H), 0.11 (s, 3H).
.sup.13 C NMR (CDCl.sub.3) .delta.: 198.5-198.1 (b, --CO's), 193.3, 190.8,
150.9, 136.6, 127.4, 111.5, 100.4, 85.2, 73.9, 38.1, 25.9, 24.4, 18.5,
-3.15, -3.35.
Preparation V. Alternative method for the preparation of compound E
Following the procedure described in Preparation II (a), a solution of the
lithium enolate was prepared from 5 mmol of
7,7-diethoxy-1-trimethylsilyl-3-heptene-1,5-diyne. To this solution
stirring at -78.degree. C. in 85 mL of solvent was added 1.15 mL (5.0
mmol) of tertbutyldimethyl silyl trifluoromethanesulfonate. The reaction
mixture was stirred for 15 min at -78.degree. C. and then removed from the
cooling bath and allowed to stir for an additional 25 min before being
poured into a mixture of 100 mL water, 70 mL ethyl acetate, 25 mL diethyl
ether, and 25 mL pentane. The mixture was extracted, and the aqueous layer
was reextracted with 100 mL of 50:50 pentane/ethyl acetate. The combined
organic extracts were washed with 75 mL saturated aqueous NaCl, dried over
Na.sub.2 SO.sub.4, concentrated in vacuo, and purified by flash
chromatography on SiO.sub.2 using 2% and then 3% ethyl acetate/hexane as
eluent to provide 1.47 g (51%) of the desired silylenol ether identical
with material prepared in Preparation II (b).
Preparation VI. Alternative methods for the preparation of compound C
(a) Alternative method A
Following the procedure of Preparation II (a), a solution of the lithium
enolate in 85 mL of solvent was prepared from 5 mmol of
7,7-diethoxy-1-trimethylsilyl-3-heptene-1,5-diyne. To this solution at
-78.degree. C. was added via syringe over a 2 min period a solution of
phenylselenium chloride (0.99 g, 5 mmol) in 6 mL of dry tetrahydrofuran
which had been precooled to -78.degree. C. The reaction mixture was
stirred for 20 min at -78.degree. C., then the cooling bath was removed,
and stirring continued for an additional 20 min. The reaction mixture was
poured into 100 mL diethylether/100 mL ethyl acetate/100 mL water and
extracted. The aqueous layer was reextracted with 50 mL 1:1
ethylether/ethyl acetate, and the combined organic extracts were washed
with 75 mL saturated aqueous NaCl, dried over Na.sub.2 SO.sub.4, and
concentrated in vacuo. Flash chromatography on SiO.sub.2 using 4% and then
5% ethyl acetate/hexane provided 1.68 g (57%) of a light brown liquid
which was a mixture of phenyselenide,
2-[[(1,1-dimethylethyl)dimethyl]silyl]oxy-2-(7,7-diethoxy-3-heptene-1,5-di
ynyl)-6-phenylseleno-cyclohexanone [compound H].
The crude mixture of selenides as dissolved in 10 mL of methylene chloride
and 0.485 mL (6.0 mmol) of pyridine was added. The solution was cooled in
an ice-water bath, and a solution of 0.82 mL (8 mmol) 30% hydrogen
peroxide in 1 mL of water was added via syringe in one portion. The
reaction mixture was stirred for 5 min, and the ice bath was removed. The
reaction mixture was stirred for 25 min, and 0.25 mL of the same hydrogen
peroxide (1 mmol) solution was added. The reaction mixture was stirred for
15 min, and 1.57 mL (7 mmol) of H.sub.2 O.sub.2 solution was added. The
reaction mixture was poured into 160 mL methylene chloride, 50 mL
saturated aqueous NaHCO.sub.3, and 50 mL water. The shaken mixture was
filtered by suction to separate the emulsion, and the layers separated.
The organic extracts were washed with 50 mL saturated aqueous NaCl, dried
over Na.sub.2 SO.sub. 4, and filtered in vacuo. Flash chromatography using
4% EtOAc/Hexane provided the desired enone whose physical properties were
consistent with the material obtained in Preparation II (c).
(b) Alternative method B
A 1.0M solution of lithium bis(trimethyl)silylamide in THF (28.7 mL, 28.77
mmol) was added to 30 mL of dry THF stirring under N.sub.2, and the
solution was cooled to -10.degree. C. A solution of 1.54 g (13.7 mmol)
1,2-cyclohexanedione in 7 mL of THF was added in a slow stream via
syringe. The reaction mixture turned dark-reddish brown. The reaction
mixture was stirred for 15 min at -10.degree. C. and then cooled to
-50.degree. C. A solution of 4-methylphenyl 4-methyl-benzenethiosulfonate
(3.5 g, 14.2 mmol) in 10 mL of THF at --50.degree. C. was added in one
portion via syringe. The reaction mixture was stirred for 2 h at
-50.degree. C. and allowed to warm at ambient temperature until
approximately 0.degree. C., and then 100 mL of 0.1N HCl was added. The
mixture was extracted with 300 mL and then 100 mL of diethyl ether, and
the combined organic extracts were dried over anhydrous sodium sulfate.
Concentration in vacuo provided a yellow solid which was purified by flash
chromatography over silica gel using CH.sub.2 Cl.sub.2, 10% EtOAc/Hexane,
and then 3% MeOH/CH.sub.2 Cl.sub.2 as eluent. The desired product,
2-hydroxy-3-[4-methylphenyl)thio]-2-cyclohexenone [compound Iy], was
isolated as a white solid (1.939 g, 60%).
Anal. calcd. for C.sub.13 H.sub.14 O.sub.2 S: C, 66.64; H, 6.02; N, 0.00.
Found: C, 66.63; H, 6.10; N, 0.00.
IR (KBr): 3372, 3054, 2954, 2920, 2870, 2834, 1642, 1600, 820, 656, 628
cm.sup.-1.
.sup.1 H NMR (CDCl.sub.3) .delta.: 7.38 (d, J=8.1 Hz, 2H), 7.16 (d, J=8.2
Hz, 2H), 6.47 (s, 1H, --OH), 2.44 (t, J=6.2 Hz, 2H), 2.35 (s, 3H), 2.17
(t, J=5.9 Hz, 2H), 1.87 (m, 2H).
.sup.13 C NMR (CDCl.sub.3) .delta.: 191.1, 143.0, 140.3, 136.0, 133 5,
130.6, 126.3, 35.4, 28.3, 22.8, 21.5.
Tert butyldimethylsilyltrifluoromethanesulfonate (TBSOTf) (20.75 mL, 90.03
mmol) was added via syringe to a solution of compound Iy (17.64 g, 75.28
mmol) and Et.sub.3 N (15.7 mL, 112.92 mmol) stirring in 250 mL of
methylene chloride under a nitrogen atmosphere at 2.degree. C. After 5
min, the cooling bath was removed, and the reaction mixture was allowed to
stir for 22 h. An additional 0.78 mL (5.59 mmol) of Et.sub.3 N followed by
0.865 mL (3.76 mmol) TBSOTf was added, and the reaction mixture was
stirred for 2 h more. The reaction mixture was poured into 200 mL of water
and 50 mL CH.sub.2 Cl.sub.2 and extracted. The organic layer was washed
with saturated aqueous brine, dried over Na.sub.2 SO.sub.4, and
concentrated in vacuo. Purification by flash chromatography over SiO.sub.2
using a 0-10% EtOAc/hexane gradient as eluent provided 21.22 g (81%) as an
off-white solid of 2-TBSoxy-3-[(4-methyl-phenyl)thio]-2-cyclohexenone
[compound J].
.sup.1 H NMR (CDCl.sub.3) .delta.: 7.38 (d, J=8.06 Hz), 2H), 7.15 (d, J=7.9
Hz, 2H), 2.35 (s, 3H), 2.38-2.34 (m, 2H), 2.12 (t, J=6.05 Hz, 2H), 1.82
(m, 2H), 1.00 (s, 9H), 21 (s, 6H).
A solution of 8.64 g (40 mmol) 80-85% pure MCPBA in 125 mL of
dichloromethane at 25.degree. C. was added via pipette to a solution of
12.7 g (36.4 mmol) compound J in 600 mL of dichloromethane at -78.degree.
C. The reaction mixture stirred for 1.75 h at -78.degree. C. and poured
into 1,100 mL of diethyl ether and 500 mL sat aq. Na.sub.2 SO.sub.3. After
extraction, the organic layer was washed successively with 300 mL and 200
mL portions of saturated aqueous NaHCO.sub.3 and then dried over sodium
sulfate. After removal of the solvent in vacuo, the crude product was
purified by flash chromatography on SiO.sub.2 using 10% and then 20%
EtOAc/Hexane as eluent to provide 12.2017 g (92%) of the corresponding
sulfoxide [compound K] as viscous, light-yellow oil.
Anal. calcd. for C.sub.19 H.sub.28 O.sub.3 SSi: C, 62.59; H, 7.49; N, 0.00.
Found: C, 62.24; H, 7.49; N, 0.06.
IR (NaCl, Film): 2954, 2930, 2886, 2858, 1694, 1610, 1080 cm.sup.-1.
.sup.1 H NMR (CDCl.sub.3) .delta.: 7.48 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.2
Hz, 2H), 2.82-2.74 (m, 1H), 2.55-2.46 (m, 1H), 2.38 (s, 3H), 2.38-2.29 (m,
1H), 2.05-1.86 (m, 3H), 0.98 (s, 9H), 0.32 (s, 3H), 0.20 (s, 3H).
.sup.13 C NMR (CDCl.sub.3) .delta.: 195.5, 142.6, 141.6, 140.5, 130.6,
124.3, 38.3, 26.1, 22.4, 21.5, 19.2, 18.5, -3.4, -4.0.
Lithium bis(trimethylsilyl)amide (40 ml of 1.0M solution in THF) was added
via syringe to a solution of 7.13 g (40.0 mmol) of
7,7-diethoxy-3-heptene-1,5-diyne stirring in 250 mL dry THF at -78.degree.
C. under a nitrogen atmosphere. The dark solution was stirred for 30 min,
and then a solution of 12.15 g (33.3 mmol) of compound K which had been
precooled to -78.degree. C. was added via cannula over 5 min. The reaction
mixture was removed from the cooling bath and allowed to stir at ambient
temperature for 1.6 h. The reaction mixture was poured into 500 mL 1N HCl
and 1 L 1:1 ether:ethyl acetate and extracted. The aqueous layer was
reextracted with two 150 mL portions of the same solvent, and the combined
organic extracts were washed with 200 mL saturated aqueous NaCl and then
dried over anhydrous Na.sub.2 SO.sub.4. Purification by flash
chromatography over SiO.sub.2 using a gradient of 10-25% EtOAc/Hexane as
eluent provided 15.5 g (86%) of a viscous brown liquid which was the
desired product as a mixture of diastereomers [compound L].
IR (NaCl, Film): 2930, 2858, 2214, 2256, 1736, 652, 1798, 1086, 1052
cm.sup.-1.
A solution of 12.02 g (22.1mmol) of compound L and 7.4 g (44.3 mmol) of
2-mercaptobenzothiazole in 100 g of heptyne was heated at reflux for 50
min, allowed to cool, and then poured into 400 mL diethyl ether and 400 mL
water. The layers were separated and the organic layer dried over
anhydrous sodium sulfate. Removal of most of the ether by rotary
evaporation caused deposition of a brown precipitate which was removed by
suction filtration and discarded. Purification of the filtrate by flash
chromatography over silica gel in the usual manner provided 4.47 g (50%)
of the desired enone which had the physical characteristics described
previously.
(c) Alternative method C
Compound D (16.96 g, 41.91 mmol) was dissolved in 400 mL of dry THF and
cooled to -78.degree.. A 1.0M solution of lithium bistrimethylsilylamide
in THF (48 mL, 48 mmol) was added via syringe over about 2 minutes. The
reaction mixture was stirred for four minutes and then the cooling bath
was replaced with an ice water bath. The reaction mixture was stirred for
1.5 h, and then allyl chloroformate (6.5 mL, 58.7 mmol) was added neat,
quickly via syringe. The reaction mixture was stirred for 1.5 h, poured
into water, and extracted with three portions of ethyl acetate. The
combined organic extracts were washed with saturated brine and then dried
over anhydrous Na.sub.2 SO.sub.4. Concentration and purification by flash
chromatography over silica gel using 4% then 5% ethyl acetate/hexane as
eluent provided the enol allylcarbonate (compound S, 16.97 g 84%) of a
slightly yellow, clear oil.
.sup.1 H NMR (CDCl.sub.3) .delta. 5.97-5.80 (m, 3H), 5.53 (t, 4.0Hz, 1 H),
5.40-5.22 (m,3H), 4.61 (m,2H), 3.75-3.68 (m, 2H), 3.63-3.55 (m, 2H),
2.27-1.99 (m, 4H), 1.79 (m, 2H), 1.21 (t, J=7.1Hz, 6H), 0.82 (s, 9H),
0.179 (s,3H), 0.173 (s, 3H).
.sup.13 C NMR (CDCl.sub.3) .delta. 153.37, 147.20, 131.38, 120.24, 118.72,
118.52, 117.30, 98.68, 91.61, 91.48, 86.49, 82.07, 68.51, 68.11, 60.77,
40.47, 25.46, 23.84, 18.82, 17.87, 14.95, -3.13, -3.56.
Anal. calcd. for C.sub.26 H.sub.40 O.sub.6 Si: C, 66.36; H, 8.25; N, 0.00.
Found: C, 66.28; H, 8.31; N, 0.00.
IR (film on NaCl) 2932, 1766, 1682, 1650 cm.sup.-1.
Acetonitrile (115 mL) was added to a flask containing Pd(OAc).sub.2 (0.1 g,
0.445 mmol) and compound S (16.47 g, 33.7 mmol) under an argon atmosphere
and a reflux condenser. The reaction mixture was heated at reflux for 3 h
and then concentrated in vacuo. Purification by flash chromatography over
silica gel using 4% then 5% ethyl acetate/hexane as eluent provided some
non polar products and then 11.2g (82%) of a colorless oil which was the
desired compound C. The spectral data of this reaction product is the same
as that reported in preparation C.
Preparation VII. Alternative method for the preparation of compound G
(a) (Z) 5-chloro-1-(2-tetrahydropyranyloxy)-4-pentene-2-yne (compound M)
Tetrahydrofuran (degassed, 600mL) was added via cannula to a flask
containing 7.55g (39.6 mmol) CuI and 5.93g (5.13 mmol)
tetrakis(triphenylphosphine)palladium(0) stirring under an argon
atmosphere. Neat cis 1,2-dichloroethylene (50 g, 516 mmol) was added via
syringe followed by 68 mL (688 mmol) of butylamine.
2-(3-propynyloxy)tetrahydropyran (48 g, 344 mmol) was added dropwise over
10 min. After the addition was complete the reaction mixture was stirred
for 10 min and then cooled in an external ice water bath for 40 min. The
cooling bath was removed and the reaction mixture allowed to stir for 4 h
at ambient temperature (25.degree. C). Air was bubbled through the
reaction mixture for 15 min and then the reaction mixture was filtered by
suction through a glass frit using pentane then ether washes for transfer.
The reaction was taken up in ethyl acetate and washed twice with water.
The aqueous layers were reextracted with ethyl acetate and the combined
organic layers dried over sodium sulfate, filtered and concentrated in
vacuo. Flash chromatography over silica gel using 2.5% then 4% ethyl
acetate/hexane as eluent provided 48.74 g (71%) of clear, slightly reddish
liquid:
.sup.1 H NMR (CDCl.sub.3) .delta. 6.33 (d,J=7.5Hz,1H), 5.84 (m,1H), 4.80
(m,1H), 4.36(m,2H), 3.78 (m,1H), 3.48 (m,1H), 1.80-1.40 (m,6H).
.sup.13 C NMR (CDCl.sub.3) .delta. 128.7, 111.6, 96.7, 93.5, 79.6, 2.0,
54.5, 30.2, 25.3, 19.0.
IR (NaCl film) 3084, 3026, 2944, 2870, 2854, 1592 cm.sup.-1.
Anal.calcd. for C.sub.10 H.sub.13 ClO.sub.2 : C, 59.86; H, 6.53. Found: C,
59.74; H, 6.44; N, 0.03.
(b) (Z) 7-(2-tetrahydropyranyloxy)-1-(trimethylsilyl)-3-heptene-1,5-diyne
(compound N)
Degassed anhydrous tetrahydrofuran (500 mL) was added to 5.86 g (4.32 mmol)
solid tetrakis(triphenylphosphine) palladium(0) and copper (I) iodide
(5.17 g, 27.1 mmol) stirring under argon. A solution of the vinyl chloride
(compound M of step (a) 45.38 g, 226.1 mmol) in 100 mL of dry
tetrahydrofuran was added via cannula followed immediately by the addition
of 45 mL (455 mmol) neat butylamine. The flask was wrapped in aluminum
foil to exclude light and then 41.6 mL (294 mmol) of trimethylsilyl
acetylene was added via syringe over 4 min. After about 10 min the
reaction became very warm and was cooled in an ice water bath for 3 min.
The cooling bath was then removed and the reaction allowed to stir for 4 h
at ambient temperature. Air was bubbled through the reaction for 15 min
and then the reaction was filtered by suction through a glass frit using
pentane then ether washes for transfer. The reaction was diluted with
ether and washed with five 500 ml portions of water. The aqueous washes
were reextracted with a small amount of diethyl ether and the combined
organic extracts were dried over anhydrous Na.sub.2 SO.sub.4, filtered,
and concentrated on a rotary evaporator. Flash chromatography over
SiO.sub.2 using 2.5% to 4% ethyl acetate/hexane as eluent provided 52.86 g
(89%) of liquid as the desired product:
.sup.1 HNMR (CDCl.sub.3) .delta. 5.83 (m,2H), 4.86 (bs, 1H), 4.44 (ABq,
Jab=14Hz,2H), 3.82 (m,1H), 3.52 (m,1H), 1.89-1.49 (m,6H), o.33(s,9H).
.sup.13 C NMR (CDCl.sub.3) .delta. 120.1, 119.7, 103.0, 101.7, 96.5, 93.4,
83.0, 61.8, 54.6, 30.2, 25.3, 18.9, -0.21.
IR (NaCl film) 2956, 2144, 844 cm.sup.-1.
Anal.calcd for C.sub.15 H.sub.22 O.sub.2 Si: C, 68.65; H, 8.45; N, 0.00.
Found: C, 68.79; H, 8.35. N, 0.06.
(c) (Z) 7-(2-tetrahydropyranyloxy)-3-heptene-1,5-diyne (compound-O)
Lithium hydroxide monohydrate (22.55 g, 0.54 mol) was added in one portion
to a solution of 21.62 g (82.38 mmol) silyl diynene (compound N of step
(b)) in 240 mL tetrahydrofuran and 40 mL water stirring at 25.degree. C.
The reaction was stirred for 1.58 h and then diluted with 1:1 ether:hexane
and water. The aqueous layer was reextracted with three portions of ether
and then the combined organic extracts were dried over anhydrous sodium
sulfate. Flash chromatography over silica gel using a gradient of 2.5 to
10% ethyl acetate/hexane as eluent provided 15.69g (98%) of brown liquid:
.sup.1 HNMR (CDCl.sub.3) .delta. 5.92 (d,J=11.OHz,1H), 5.78 (dd,J=11.1,
2.2Hz,1H), 4.87 (m,1H), 4.45 (tallmultiplet, 2H), 3.83 (m,1H), 3.52
(m,1H), 3.30 (d,J=2.1Hz,1H), 1.79-1.48 (m,6H).
.sup.13 CNMR (CDCl.sub.3) .delta. 121.2, 118.7, 96.6, 93.5, 84.7, 82.7,
80.5, 62.0, 54.6, 30.2, 25.4, 19.0.
IR (NaCl film) 3288, 2944, 2870, 2854, 2096 cm-1.
Anal calcd for C.sub.13 H.sub.14 O2=C, 75.76; H, 7.42. Found=C, 75.22; H,
7.30.
(d) (Z)
6-[[(1,1-dimethylethyl)dimethylsilyloxy]-6-[7-(2-tetrahydropyranyloxy)-3-h
eptene-1,5-diynyl]-2-cyclohexenone (compound P)
A 1.0M solution of lithium bis(trimethylsilylamide) in tetrahydrofuran (89
mL, 89 mmol) was added via syringe to a solution of 15.4 g (80.9 mmol)
diynene (compound O of step (c)) in 500 mL of tetrahydrofuran stirring at
-78.degree. C. under an atmosphere of nitrogen. The reaction was stirred
for 35 min and then a solution of 24.6 g (67.46 mmol) sulfoxide ketone
(compound K) in 100 mL of tetrahydrofuran at -70.degree. C. was added via
cannula. The cooling bath was removed and the reaction was allowed to stir
at ambient temperature for 2 h (gradually reaching 25.degree. C). The
reaction was quenched with saturated aqueous ammonium chloride and
extracted with two portions of 1:1 ethyl acetate:ethyl ether. The combined
organic extracts were washed with saturated aqueous sodium bicarbonate
then saturated sodium chloride, dried over sodium sulfate, and
concentrated in vacuo. Purification by flash chromatography over silica
gel using a gradient of 2.5 to 20% ethyl acetate/hexane as eluent provided
27.3 g (73%) of viscous oil which was the desired keto sulfoxides as a
mixture of diastereomers.
A solution of 27.3 g (49.2 mmol) of the sulfoxide from above in 540 mL of
pyridine was heated at 105.degree. C. for 1.75 h and then diluted with
toluene (several portions were added to help remove the pyridine
azeotropically) and concentrated on a rotary evaporator. The crude product
was purified by flash chromatography using 5 then 10% ethyl acetate/hexane
as eluent to provide 18.Og (88%) of a light yellow oil which was the
desired product contaminated with trace amounts of sulfur byproducts. This
material was used directly in the next alcohol deprotection reaction:
.sup.1 HNMR (CDCl.sub.3) .delta. 6.89-6.82 (m,1H), 5.96
(dd,J=10.9,1.2Hz,1H), 5.87-5.77 (m,2H), 4.78 (m,1H), 4.46-4.31 (m,2H),
3.81(m,1H), 3.51 (m,1H), 2.70-2.64 (m,1H), 2.47-2.39 (m,1H), 2.29-2.14
(m,2H), 1.81-1.49 (m.6H), 0.68 (s,9H), 0.20 s,3H), 0.18 (s,3H).
(e) (Z)
6-[[1,1-dimethylethy)dimethylsilyl]-6-[(7-hydroxy)-3-heptene-1,5-diynyl]-2
-cyclohexenone (compound Q)
Para-toluenesulfonic acid (1.21 g, 6.36 mmol) was added to a solution of
the tetrahdropyranyl ether (compound P of step (d) 18.Og, 43.3 mmol) in
200 mL of methanol stirring at 25.degree. C. The reaction was stirred for
30 min and then concentrated on a rotary evaporator. The crude oil was
taken up in ethyl acetate and washed with saurated aqueous NaHCO.sub.3 and
then saturated aqueous NaCl. The organic extracts were dried over
anhydrous sodium sulfate and then concentrated in vacuo. Purification by
flash chromatography over silica gel using a gradient of 5%-20% ethyl
acetate/hexane as eluent provided 10.75 g (75%) of the desired product as
a light yellow oil:
.sup.1 HNMR (CDC1.sub.3) 6.91 (m,1H), 5.98 dt,J=10.3,1.9Hz,1H), 5.88
(dt,J=10.8,0.6Hz,1H), 5.80 (d,J=10.7Hz,1H), 4.40 (d,J=6.2Hz,2H), 2.5-2.20
(m,4H), 1.59 (s.1H), 0.85 (s,9H), 0.20 (s,3H), 0.18 (s,3H).
.sup.13 C NMR (CDCl.sub.3) 194.3, 150.7, 127.0, 121.0, 119.0, 95.9, 94.3,
84.8, 82.6, 72.9, 51.3, 38.3, 25.5, 24.5, 18.0, -3.5, -3.6.
(f) Cobalt, hexacarbonyl [.mu.-[6-[5,6 .eta.:5,6.eta.)-(Z)
6-[[(1,1-dimethylethy)dimethylsilyl]-6-[(7-hydroxy)-3-heptene-1,5-diynyl]-
2-cyclohexenone, di(Co-Co) (compound R)
Octacarbonyldicobalt (Alfa, 4.41 g, 12.9 mmol) was added in one portion to
a solution of 4.27 g (12.9 mmol) enone alcohol (compound Q of step (e))
stirring in 170 mL of dichloromethane at 25.degree. C. under an atmosphere
of nitrogen. The reaction was stirred for 2 h and then concentrated on a
rotary evaporator. Purification by flash chromatography over silica gel
using a gradient of 5 to 20% ethyl acetate/hexane provided 6.18 g (78%) of
the desired product as a purple oil:
.sup.1 H NMR (CDCl.sub.3) .delta. 6.91 (m,1H), 6.72 (d,J=10.7Hz,1H), 6.01
(broad doublet,J=10.1Hz,1H), 5.77 (d,J=10.6Hz,1H), 4.85 (d,J=6.5Hz,2H),
2.56 2 30 (m,2H), 2.27 (t,J=5.6Hz,2H), 1.50 (bs,1H), 0.85 (s,9H), 0.19
(s,3H), 0.074 (s,3H).
A slower eluting minor isomer (1.29g, 16%) was also isolated and is the
cobalt complex of the other acetylene of the diynene.
(g) Compound G
A 2.0M solution of ethylmagnesium bromide in tetrahydrofuran (6.50 mL, 13
mmol) was added dropwise to a solution of t-butanal (1.29mL, 13.5mmol) in
30 mL of dry tetrahydrofuran at 0.degree. C. The reaction was stirred for
15 min and then the cooling bath was removed. After 5 min a solution of
the cobalt complexed alcohol (compound R of step (f) 6.18 g, 10.03 mmol)
was added via cannula. A solution of 3.39 g (13.4 mmol)
1,1'-(azodicarbonyl)-dipiperidine in 30 mL dry tetrahydrofuran was added
dropwise via cannula. After the addition was complete the reaction was
poured into a saturated aqueous brine solution and extracted. The organic
layer was washed with saturated aqueous sodium bicarbonate and then
saturated aqueous brine. The combined aqueous washes were extracted once
with 1:1 ethyl acetate: ethyl ether and then the combined organic extracts
were dried over anhdrous sodium sulfate and concentrated in vacuo. Flash
chromatography using 10% ethyl acetate/hexane provided 5.57 g (89%) of
reddish purple viscous oil.
Preparation VIII. Preparation of dimethylphenylthiol aluminum
A solution of 1.0 mL of 2.0M trimethylaluminum in hexanes was added
dropwise over 0.5 min to a solution of 0.2054 mL (2.0 mmol) thiophenol
stirring in 2 mL dry hexane under a nitrogen atmosphere in an ice water
cooling bath.
The reaction mixture was stirred for 30 min, and then 6 mL of dry
tetrahydrofuran was added via syringe.
Preparation X. Preparation of 2-quinoxalyl isocyanate
Diphenylphosphoryl azide (1.23 mL) was added to a solution of triethylamine
(800 ul) and 2-quinoxaline carboxylic acid 1 g (5.74 mmol) stirring in 10
mL of dry dimethylformamide in an icewater cooling bath (2.degree.). The
reaction was stirred for 2.33 h during which time the reaction was allowed
to warm to 25.degree.. The reaction was poured into ice water and
extracted three times with diethyl ether. The combined organic extracts
were dried over anhydrous sodium sulfate, filtered, and then concentrated
in vacuo. The crude azide was dissolved in 15 mL of benzene and heated at
reflux for 1.5 h. The solvent was removed in vacuo to provide the desired
solid isocyanate. FT IR indicated a strong isocyanate absorption.
The following examples are provided to more fully illustrate the invention
and are not to be construed as limiting the scope of the invention in any
manner.
EXAMPLE 1
Cobalt, hexacarbonyl[.mu.-](6,7-.eta.)-1-[[(1,1-dimethylethyl)
dimethylsilyl]oxy]-8-hydroxy-10-phenylthio-bicyclo[7.3.1]tridec-4-ene-2.6-
diyn-13-one]]di (Co-Co)
##STR20##
A previously prepared stock solution of dimethyl-(phenylthio)aluminum (6.85
ml, 1.49 mmol) was added in one portion via syringe to a solution of enone
cobalt complex aldehyde (compound G, 297 mg, 0.483 mmol) in 11 mL of dry
tetrahydrofuran stirring under a nitrogen atmosphere at -50.degree. C. The
reaction mixture was stirred for 15 min and then cooled to -78.degree. C.
The reaction mixture was then allowed to warm to -50.degree. C. over 90
min, and neat titanium isopropoxide (1.0 mL, 3.34 mmol) was added thereto
in one portion via syringe. The reaction mixture was stirred for 15 min at
a temperature between -50.degree. C. and -45.degree. C., and then an
additional 2.0 mL (6.68 mmol) of neat titanium isopropoxide was added. The
reaction mixture was stirred for 15 min between -50.degree. and
-45.degree. C. and then 20 min between -45 .degree. and -40.degree. , and
then an additional 2.0 mL (6.68 mmol) of titanium isopropoxide was added.
The reaction mixture was stirred for 15 min between -40.degree. C. and
-30.degree. C. and then recooled to -65.degree. . The reaction mixture was
allowed to warm to -55.degree. over 30 min, and then the cooling bath was
removed. The reaction mixture was stirred for 20 min at ambient
temperature and then poured into 300 ml of ethyl acetate and 100 mL of
water and extracted. The aqueous layer was reextracted with 100 ml of
ethyl acetate, and the combined organic layers were washed with 100 ml
saturated aqueous NaCl solution and then dried over anhydrous Na.sub.2
SO.sub.4. After filtration and concentration in vacuo, the crude product
was purified by flash chromatography on SiO.sub.2 to provide four
fractions of material described in their order of elution from the column:
Fraction 1 contained 56 mg (16%) of purple viscous oil which was an
aldehyde resulting from simple conjugate addition of phenylmercaptan;
fraction 2 contained 68.2 mg (23%) of pure recovered starting material;
and fraction 3 contained a 6:4 mixture of the desired product and starting
material (59 mg, 11% desired, 6% starting material).
Fraction 4 provided 142 mg (41%) of the desired title compound as a
reddish-purple foam.
IR (KBr): 3442, 3060, 2954, 2930, 2894, 2858, 2096, 2060, 2029, 1730, 1080,
838, 780, 744 cm.sup.-1.
.sup.1 H NMR (CDCl.sub.3) .delta.: 7.50-7.47 (m, 2H), 7.36-7.24 (m, 3H),
7.03 (d, J=9.9 Hz, 1H), 5.79 (d, J=9.9 Hz, 1H), 5.29 (bt, J=7.5 Hz, 1H),
4.32 (bs, 1H), 2.77 (d, J=9.2 Hz, 1H), 2.51-2.38 (m, 2H), 2.28-2.27 (m,
1H), 1.98-1.93 (m, 1H), 1.38 (d, J=7.5 Hz, 1H, --OH), 0.83 (s, 9H), 0.19
(s, 3H), 0.13 (s, 3H).
.sup.13 C NMR (CDCl.sub.3) .delta.: 199.1 (b), 198.3, 142.4, 133.7, 129.7,
128.4, 110.5, 99.2, 97.4, 92.1, 82.6, 69.4, 62.6, 48.5, 37.1, 25.9, 23.4,
18.5, -2.6, -2.9.
EXAMPLE 2.
8-Hydroxy-1-TBSoxy-bicyclo[7.3.1]trideca-4,9-diene-2.6-diyn-13-one
##STR21##
(a) Preparation of
1-[[(1,1-dimethylethyl))dimethylsilyl]oxy]-8-hydroxy-10-phenylthio-bicyclo
[7.3.1]tridec-4-ene-2,6-diyn-13-one
##STR22##
Iodine crystals 12 mg, 0.095 mmol) were added to a solution of cobalt
complex reaction product of Example 1 (19 mg, 0.026 mmol) in 5 mL of dry
benzene stirring under a nitrogen atmosphere at 25.degree. C. The reaction
mixture was stirred for 2 h, concentrated slightly in vacuo, and then
flash chromatographed on SiO.sub.2 using 4% ethyl acetate/hexane as eluent
to provide 6 mg (53%) of the desired decomplexed substrate as a clear oil.
FAB MS (NOBA): M.sup.+ 438.
IR Neat (NaCl, Film): 3484, 3060, 2954, 2958, 2208(w), 1714, 1584
cm.sup.-1.
.sup.1 H NMR (CDCl.sub.3) .delta.: 7.48-7.38 (m, 2H), 7.36-7.31 (m, 3H),
5.92 (s, 2H), 5.25 (dd, J=11.0, 4.5 Hz, 1H), 4.43 (d, J=11.0 Hz, 1H,
--OH), 4.05 (dt, J=5.5, 9.8 Hz, 1H), 2.81 (dd, J=10.1, 4.6 Hz, 1H), 2.43
(m, 1H), 2.29 (m, 1H), 2.10 (m, 1H), 1.91 (m, 1H), 0.88 (s, 9H), 0.19 (s,
3H), 0.17 (s, 3H).
.sup.13 C NMR (CDCl.sub.3) .delta.: 207.1, 134.7, 132.6, 129.8, 129.0,
125.1, 23.6, 99.6, 98.0, 92.9, 85.0, 74.4, 65.7, 59.1, 43.1, 34.7, 26.9,
25.9, 18.4, -2.9, -3.0.
(b) Preparation of
1-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-8-hydroxy-bicyclo[7.3.1]trideca
-4,9-diene-2,6-diyn-13-one
Solid sodium periodate (120 mg, 0.56 mmol) was added to a solution of the
product of step (a) above (5 mg, 0.011 mmol) in 5 mL methanol and 2 mL
water at 25.degree. C. The reaction mixture was stirred for 10 min, and 1
mL of water was added to dissolve the precipitate, and the stirring
continued for 90 min. An additional 149 mg (0.70 mmol) of sodium periodate
was added, and the reaction mixture stirred for 45 min and extracted with
50 mL of methylene chloride and 5 mL of water. The aqueous layer was
reextracted with 10 mL of methylene chloride. The combined organic layers
were dried over anhydrous Na.sub.2 SO.sub.4, concentrated in vacuo, and
flash chromatographed on SiO.sub.2 using 10% ethyl acetate/hexane as
eluent to provide two fractions:
Fraction 1 provided less than 1 mg of a minor, faster eluting side product.
Fraction 2 provided 2 mg (56%) of the desired title compound as a white
solid.
FAB MS (NOBA): (M+H) 329.
IR Neat (NaCl) 3356, 2952, 2928, 2856, 1712, 1690, 1414, 782 cm.sup.-1.
.sup.1 H NMR (CDCl.sub.3) .delta.: 6.37 (bs, 1H), 5.84 (s, 2H), 5.22 (d,
J=10.8 Hz, 1H), 4.82 (d, J=10.8 Hz, 1H, --OH), 2.51-2.47 (m, 2H),
2.28-2.25 (m, 1H), 2.16-2.10 (m, 1H), 0.91 (s, 9H), 0.22 (s, 3H), 0.19 (s,
3H).
.sup.13 C NMR (CDCl.sub.3) 196.8, 139.4, 137.2, 124.8, 123.1, 101.4, 96.3,
93.0, 87.7, 74.6, 69.2, 34.6, 26.0, 24.8, 18.5, -2.8, -3.1.
EXAMPLE 3
Alternative preparations of compound of Example 2
(a) Alternative method A
Solid 3-chloroperbenzoic acid, (mCPBA, 10.3 mg, 0.059 mmol) was added to a
solution of the product of Example 1 (23.4 mg, 0.032 mmol) in 10 ml of
methylene chloride at 25.degree. C. The reaction mixture was stirred for
15 min, and an additional 14.9 mg (0.086 mmol) was added. The reaction
mixture was stirred for another hour during which 6.2 mg (0.035 mmol) more
of mCPBA was added. The reaction mixture was poured into approximately 20
ml of methylene chloride and 10 ml of saturated solution of NaHCO.sub.3.
The aqueous layer was extracted with methylene chloride and the organic
layer washed with saturated solution of NaCl, and the combined organic
layer was dried over anhydrous Na.sub.2 SO.sub.4 and concentrated in
vacuo. Flash chromatography on SiO.sub.2 using 5% ethylacetate/hexane as
eluent provided 4.6 mg (43%) of the desired product as an off-white solid.
(b) Alternative method B
A solution of 0.595 g (3.45 mmol) of 85% pure MCPBA in 15 mL of CH.sub.2
Cl.sub.2 was added dropwise via pipet to a solution of 2.0 g (2.76 mmol)
of the product of Example 1 in 100 mL of CH.sub.2 Cl.sub.2 stirring at
-78.degree. under a nitrogen atmosphere. The reaction mixture was stirred
for 30 min at -78.degree. and then removed from the cooling bath.
Immediately, 50 mL of 1-hexyne was added and then the reaction mixture was
allowed to stir for 1.33 h at ambient temperature. The reaction mixture
was then poured into a mixture of 400 mL CH.sub.2 Cl.sub.2, 200 mL water,
and 100 mL sat. aq. NaHCO.sub.3. After extraction the aqueous layer was
reextracted with two 150 mL portions of CH.sub.2 Cl.sub.2. The combined
organic extracts were washed with 200 mL of saturated brine, dried over
sodium sulfate, and concentrated in vacuo. The resulting red oil was
dissolved in 60 mL of acetone which contained 0.15 mL (1.08 mmol) of
triethylamine A single portion of cerric ammonium nitrate (CAN, 4.5 g,
8.21 mmol) was added and the reaction was sttirred for 35 min. An
additional 1.00 g (1.82 mmol) of CAN was added and the reaction mixture
was stirred for 15 min longer. The reaction mixture was poured into 500 mL
of ethyl acetate and 200 mL of water and extracted. The aqueous layer was
reextracted with three 100 mL portions of ethyl acetate and then the
combined organic extracts were washed with 100 mL sat. aq. brine. The
solution was dried over sodium sulfate, filtered, concentrated in vacuo
and placed on top of a 8 inch.times.1.7 inch flash column of silica gel.
Elution with 3-10% ethyl acetate/hexane provided, after concentration in
vacuo, 504 mg (56%) of the desired enone as a white solid.
EXAMPLE 4
1,8-Dihydroxy-bicyclo[7.3.1]trideca-4.9-diene-2.6-diyn-13-one
(a) Alternative method A
##STR23##
Trifluromethanesulfonic acid (2 drops from a 22 gauge needle, 0.010 mL,
0.11 mmol) was added to a solution of
8-hydroxy-1-TBSoxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-13-one
(product of Example 2, 12.2 mg, 0.040 mmol) in 7 mL of dichloromethane
containing 800 mg of 4A molecular sieves stirring at 25.degree. C. The
reaction mixture was stirred for 10 minutes, diluted with 50 mL
dichloromethane, and washed with 50 mL of saturated aqueous sodium
bicarbonate. The organic layer was concentrated in vacuo. The crude
product thus obtained was combined with the crude product from a similar
experiment in which 2.5 mg of the enone alcohol was utilized. Flash
chromatography of the combined crude product over silica gel using 10% and
then 20% ethyl acetate/hexane as eluent provided 8.6 mg (83%) of the
desired product as a white stable solid.
MS: m/e 214.
.sup.1 H NMR CDCl.sub.3) 6.51 (m, 1H), 5.84 (s, 2H), 5.23 (d, J=11.2 Hz,
1H), 4.38 (d, J=11.2 Hz, 1H, --OH), 3.93 (s, 1H, --OH), 2.58-2.51 (m, 2H),
2.46-2.39 (m, 1H), 2.13-2.01 (m, 1H).
.sup.13 C NMR (CDCl.sub.3) .delta.: 195.8, 141.1, 135.8, 124.3, 122.9,
100.2, 95.7, 91.5, 87.6, 72.0, 68.4, 31.4, 24.1.
Anal. calcd. for C.sub.13 H.sub.10 O.sub.3 : C, 72.89,; H, 4.71 Found: C,
73.06; H, 4.95.
(b) Alternative method B
A 48% aqueous solution of HF (0.5 mL) was added to a stirred solution of 15
mg (0.046 mmol) of silyl enone in 1.5 mL of CH.sub.3 CN at 25.degree.
under a nitrogen atmosphere. The reaction mixture was stirred for 5 min at
25.degree.. TLC (20% EtOAc/hexane on SiO.sub.2) showed only starting
material. The reaction mixture was heated to reflux and then refluxed for
5 min. The heat source was then removed and the reaction mixture was
allowed to stir for 15 min at ambient temperature. The reaction mixture
was poured into 40 mL of CH.sub.2 Cl.sub.2 and 40 mL water. The mixture
was extracted and the aqueous layer was reextracted with an additional 20
mL portion of CH.sub.2 Cl.sub.2. The combined organic extracts were washed
with 20 mL of saturated aqueous brine, dried over sodium sulfate, and
concentrated in vacuo. Flash chromatography on SiO.sub.2 using 30% then
50% diethyl ether/pentane as eluent provided 8.7 mg (89%) of a white solid
which was the desired desilylated diol.
EXAMPLE 5
8-Acetoxy-1-hydroxy-bicyclo[7.3.1]trideca-4.9-diene-2,6-diyn-13-one
##STR24##
To a solution of
1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-13-one (product of
Example 4, 32 mg, 0.149 mmol) in 1 ml of pyridine Was added
dimethylaminopyridine and 1 eq of acetic anhydride (14 ul, 0.149 mmol).
The reaction mixture was stirred at ambient temperature for 30 minutes and
then pyridine was stripped off on rotovap and on high vacuum. This residue
was purified on a silica gel column using 10% and 20% ethyl acetate/hexane
mixture as the solvent system. The title compound was obtained as light
yellow foam in 85% yield (32.4 mg).
IR (KBr): 3450, 3058, 2926, 2856, 2196, 1742, 1710, 1634, 1418, 1342 .sup.1
H NMR(CDCl.sub.3): .delta. 2.07 (1H, m), 2.18 (3H, s), 2.43 (1H, m), 2.56
(2H, m), 4.12 (1H, s), 5.86 (2H, q), 6.11 (1H, s), 6.69 (1H, t)
.sup.13 C NMR(CDCl.sub.3): .delta. 21.069, 24.410, 32.090, 68.547, 72.456,
90.591, 90.822, 96.120, 97.016, 123.980, 124.846, 134.952, 143.671,
171.210, 192.392
MS: 257 (M+), 239, 215, 169
EXAMPLE 6
1-Hydroxy-8-[[(2-quinoxoly)carbony]oxy]-bicyclo
[7.3.1]trideca-4.7-diene-2.6-diyn-13-one
##STR25##
Solid 2-quinoxaloyl chloride (25 mg, 0.13 mmol) was added to a solution of
4-(N,N-dimethylamino)pyridine (32 mg, 0.26 mmol) and the product of
Example 4 (19 mg, 0.089 mmol) in 2 mL pyridine stirring at 25.degree.
under an atmosphere of N.sub.2. The reaction mixture was stirred for 30
min and then an additional 25 mg (0.13 mmol) of the acid chloride was
added. The reaction mixture was stirred for another hour and then poured
into 100 mL of ethyl acetate and 50 mL of water. The mixture was extracted
and the aqueous layer was rextracted with two 25 mL portions of ethyl
acetate. The combined organic extracts were washed with 50 mL sat. aqueous
brine and dried over sodium sulfate. Concentration in vacuo followed by
flash chromatography over silica gel using a 20-50% ethyl acetate/hexane
gradient provided the title compound (29 mg 88%) as a white solid:
DCI MS: MH.sup.+ =371
IR KBr) 3470(b), 2194, 1726, 1696, 1228 cm.sup.-1.
.sup.1 H NMR (CDCl.sub.3) .delta.: 9.68 (bs,1H), 8.34 (d, J=7.9 Hz, 1H),
8.20 (d, J=8.0 Hz, 2H), 7.89 (m, 2H), 6.84 (bs, 1H), 6.53 (s, 1H), 5.94
(ABq, J.sub.AB =9.61 Hz, 2H), 4.13 (bs, 1H), 2.66-2.61 m, 2H), 2.51 (m,
1H), 2.16-2.05 (m, 1H).
.sup.13 C NMR (CDCl.sub.3) .delta.: 192.16, 189.74, 145.98, 144.09, 134.60,
133.14, 131.60, 130.08, 125.30, 123.95, 97.12, 95.49, 91.76, 90.65, 72.49,
69.99, 32.14, 24.52.
EXAMPLE 7
1-Hydroxy-8-[[(2,2.2-trichloroethoxy)-carbonyl]oxy]-bicyclo[7.3.1]trideca-4
.9-diene-2.6-diyne-13-one
##STR26##
To a solution of the product of Example 4 (7.3 mg, 0.034 mmol) in 500 ul of
pyridine was added trichloroethyl chloroformate (5 ul, 0.03 mmol).
Additional trichloroethyl chloroformate and pyridine (500 ul) were added.
The reaction mixture was stirred at ambient temperature for 1 hour and 10
minutes, washed with saturated solution of sodium chloride, and the
aqueous layer extracted 3 times with methylene chloride. The combined
organic layer was dried over sodium sulfate and concentrated in vacuo. The
residue was purified on a silica gel column using ethyl acetate/hexane as
the solvent system to yield the title compound (3.3 mg, 25% yield).
.sup.1 H NMR (CDCl.sub.3) 2.08 (1H, m), 2.40 (1H,m), 2.60 (2H, m), 4.11
(1H, s), 4.78 (2H, d), 5.91 (2H, dd), 6.06 (1H, s), 6.69 (1H, t)
MS: 197, 169
EXAMPLE 8
1-Hydroxy-8-[[(2-quinoxolyamino)carbonyl]-oxy]-bicyclo[7.3.1
]trideca-4,7-diene-2,6-diyn-13-one
##STR27##
To a solution of
8-hydroxy-1-TBSoxy-bicyclo[7.3.1]-trideca-4,9-diene-2,6-diyn-13-one
(product of Example 2, 137 mg, 0.419 mmol) in 10 ml of pyridine was added
in portions 2.8 eq of quinoxaline-2-isocyanate (prepared by the method
described in), first 140 mg, then 60 mg in an additional 2 ml of pyridine.
To this was added dimethylamino pyridine (25 mg, 0.2 mmol). The reaction
mixture was stirred at ambient temperature under nitrogen for 4 hours,
washed with water, and the aqueous layer extracted twice with diethyl
ether. The combined organic layer was dried over sodium sulfate and
concentrated in vacuo. This residue was purified on a silica gel column
using a gradient of 5% to 20% ethyl acetate/hexane mixture as the solvent
system. The 1-TBS protected title compound was obtained as a yellow powder
in 74% yield (44.1 mg, based on recovered starting material).
A solution of the 1-TBS protected title compound (40 mg, 0.08 mmol) in 16
ml of anhydrous methylene chloride and 1.8 g 4.ANG. molecular sieves was
stirred at ambient temperature under nitrogen for 10-15 minutes. To this
mixture was added 2.8 eq of trifluoromethanesulfonic acid (first 15 ul,
then 5 ul, 0.226 mmol). The reaction is complete upon addition of the
trifluoromethanesulfonic acid. Saturated solution of sodium bicarbonate
was added to the reaction mixture and the aqueous layer was extracted
three times with methylene chloride. The combined organic layer was washed
with saturated solution of sodium chloride, dried over sodium sulfate and
concentrated in vacuo.
The solid residue was then triturated with 5% ethyl acetate/hexane mixture.
The title compound was obtained as light yellow crystals and film in 97%
yield (30.4 mg).
.sup.1 H NMR (CDCl.sub.3) 2.07 (1H, m), 2.47 (1H, m), 2.61 (2H, m), 4.23
(1H, s), 5.89 (2H, q), 6.26 (1H, s), 6.76 (1H, t), 7.65 (2H, m), 7.84
(1H,d), 8.04 (1H, d), 9.62 (1H, s)
EXAMPLE 9
1-Hydroxy-8-[[(3-pyridylamino)carbony]oxy]-bicyclo[7.3.1]trideca-4,9-diene-
2,6-diyne-13-one
##STR28##
Pyridine 3-isocyanate (disclosed in U.S. Pat. No. 3,342,545, 56 mg, 0.464
mmol) was added to a solution of the product of Example 4 (28.9 mg, 0.135
mmol) in 4 mL of dry benzene. The reaction vessel was placed in an oil
bath and the bath temperature was raised from 25.degree. to 90.degree.
over 15 min. The reaction mixture was stirred for 1.1 h and then an
additional 15 mg (0.125 mmol) of pyridine 3-isocyanate was added. The
reaction mixture was stirred for 0.9 h more and then concentrated in
vacuo. Purification over silica gel using a diethyl ether/hexane gradient
as eluent provided the title compound (17.9 mg) as an offwhite solid.
.sup.1 H NMR (drop DMSO-d.sub.6 in CDCl.sub.3) .delta.9.59 (bs, 1H), 8.56
(bs, 1H), 8.08 (bs, 1H), 7.75 (d, J=6Hz, 1H), 7.03 (m, 1H), 6.56 (m, 1H),
6.05 (s, 1H), 5.75 (d, J=10.4Hz, 1H), 5.66 (dd, J=1.1, 10.4Hz, 1H), 4.76
(bs, 1H), 2.2I (m,2H), 2.24 (m, 1H), 1.89 (m, 1H).
EXAMPLE 10
1-Hydroxy-8-[[(N,N-diethlyamino)carbony]-oxy]-bicyclo[7.3.1]trideca-4,9-die
ne-2,6-diyne-13-one
##STR29##
A solution of 1.90M phosgene in toluene 0.1 mL) was added to a stirtred
solution of the product of Example 2 (12.5 mg, 0.038 mmol) and 26.5 ul
(0.19 mmol) triethylamine in 1.5 mL CH.sub.2 Cl.sub.2 at 25.degree.. The
reaction mixture was stirred for 1.5h and then 25 ul (0.238 mmol) of
diethylamine was added. After 10 min, the reaction mixture was poured into
CH.sub.2 Cl.sub.2 and water and extracted three times with methylene
chloride. The combined organic extracts were washed with aqueous brine,
dried over Na.sub.2 SO.sub.4, and concentrated in vacuo to provide a tan
solid.
The tan solid was dissolved in 6 mL of dry tetrahydrofuran and (25 ul,
0.025 mmol) of a 1.0M solution of tetra n-butylammonium fluoride in
tetrahydrofuran was added. The reaction began to darken immediately but
was allowed to stir for 1 h. The reaction mixture was poured into CH.sub.2
Cl.sub.2 and water and extracted. The aqueous layer was reextracted once
with dichloromethane and once with ether and then the combined organic
extracts were dried over sodium sulfate. The reaction was concentrated in
vacuo and purified by flash chromatography over silica gel to provide 2 mg
of carbamate which was still silylated and a second fraction which
contained mainly the title compound. This material was filtered through a
small pad of silica gel to provide after concentration in vacuo 2.3 mg of
white solid.
.sup.1 H NMR (CDCl.sub.3) .delta. 6.65 (m, 1H), 6.15 (s,1H), 5.85 (ABq,
JAB=8.2Hz, 2H), 4.12 (s, 1H), 3.39-3.29 (m, 4H), 2.55 (m,1H), 2.50-2.39
(m,1H), 2.10-2.00 (m,2H), 1.19 (t, J=7.69Hz, 3H), 1.11 (t, J=7.03Hz, 3H)
EXAMPLE 11
1-Hydroxy-8-[[(methlyamino)carbonyl]oxy]-bicyclo[7.3.1]trideca-4,9-diene-2,
6-diyne-13-one
##STR30##
To a solution of the product of Example 2 (10.4 mg, 0.032 mmol) in 800 ul
of pyridine was added methyl isocyanate (11 ul, 0.19 mmol) and
dimethylaminopyridine. The reaction mixture was stirred at ambient
temperature for about 3 hours at which time additional methyl isocyante
(15 ul, 026 mmol) as added. The reaction mixture was stirred overnight (23
hours) at ambient temperature, washed with water, and the aqueous layer
extracted twice with methylene chloride and once with ether. The organic
layer was dried over sodium sulfate and then concentrated in vacuo. The
residue was then purified on a silica gel pipet column and eluted with 5%,
10%, 20%, 35% ethyl acetate/hexane to provide the 1-TBS protected title
compound (3.8 mg, 31% yield).
To solution of the 1-TBS protected title compound (3.8 mg, 0.009 mmol) in 4
ml of methylene chloride was added 600 mg of 4A molecular sieves, and the
mixture was stirred for 10 minutes at ambient temperature. To this was
added trifluoromethanesulfonic acid (2 ul, 0.022 mmol) and the reaction
was stopped immediately with a saturated solution of sodium bicarbonate.
The aqueous layer was extracted twice with methylene chloride and the
organic layer was then washed with saturated solution of sodium chloride,
dried over sodium sulfate and concentrated in vacuo. The residue was
purified on a silica gel column and eluted with 5%, 10%, 20%, 35% ethyl
acetate/hexane to provide the title compound in nearly quantitative yield
(3.2 mg).
.sup.1 H NMR (CDCl.sub.3): 2.05 (1 H,m), 2.45 (1H, m), 2.57 (2H, m), 2.80
(3H, d), 4.12 (1H, s), 4.93 (1H, bs), 5.86 (2H, dd), 6.16 (1H, s), 6.69
(1H, t)
MS: 272 (MH+), 254, 228, 215, 197, 187, 169, 154, 141
EXAMPLE 12
1-Hydroxy-8-[[[(t-butoxycarbonyl)amino]-pentyl
aminocarbonyl]oxy]-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyne-13-one
##STR31##
To a solution the product of Example 2 (20.3 mg, 0.06 mmol) in 1 ml of
pyridine was added a solution of 5-(t-BOC amino)-pentylisocyanate in 500
ul of pyridine and dimethylamino pyridine. The reaction mixture was
stirred at ambient temperature for 3 hours, washed with water, and the
aqueous layer extracted 4 times with methylene chloride. The organic layer
was dried over sodium sulfate and concentrated in vacuo. The residue was
purified by flash column chromatography on a silica gel column and eluted
with 5%, 10%, 20% ethyl acetate/hexane. The 1-TBS protected title compound
was obtained as a yellow oil in 90% yield (31 mg).
The 1-TBS protected title compound (10.3 mg, 0.018 mmol) was dissolved in
1.2 ml of tetrahydrofuran. To this solution was added 6 ul of acetic acid
and of tetrabutylammonium fluoride (10 ul, 0.01 mmol). Additional
tetrabutylammonium fluoride (190 ul, 0.19 mmol) was added over a 45
minutes period. The reaction mixture was washed with water and the aqueous
layer extracted 3 times with ether. The organic layer was dried over
sodium sulfate and concentrated in vacuo. The residue was purified on a
silica gel column and eluted with ethyl acetate/hexane to provide the
title compound (1 mg).
.sup.1 H NMR (CDCl.sub.3): 1.31-1.60 (6H, m), 1.4 (9H, s), 2.06 (1H, s),
2.43 (1H, m), 2.57 (2H, m), 3.13 (4H, m), 4.14 (1H, bs), 4.58 (1H, bs),
5.03 (1H, bs), 5.87 (2H, dd), 6.11 (1H, s), 6.68 (1H, t)
The t-BOC amino protecting group may be removed using a known deblocking
reagent such as hydrochloric acid, trifluoroacetic acid, trimethylsilyl
iodide, trimethysilyl chloride, trimethylsilyl triflate, and aluminum
chloride, to give 1-hydroxy-8-[[(aminopentyl
aminocarbonyl]oxy]-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyne-13-one.
EXAMPLE 13
1,8-Dihydroxy-bicyclo[7.3.1]trideca-2,6-diyne-9,10-epoxy-4-ene-13-one
##STR32##
To a solution of the product of Example 2 (113.2 mg, 0.344 mmol) in 13 ml
of methylene chloride was added 1.5 eq of triethylamine (75 ul, 0.516
mmol) and 1.2 eq of tert-butyl dimethylsilyl trifluoromethanesulfonate (95
ul, 0.413 mmol). The reaction mixture was stirred at ambient temperature
for 18 minutes, washed with water, and the aqueous layer extracted 2 times
with methylene chloride. The organic layer was dried over sodium sulfate
and concentrated in vacuo. The residue was purified by flash column
chromatography on a silica gel column eluting with ethyl acetate/hexane to
give the 1,8-bis(TBS)-protected starting material as a yellow solid in 94%
yield (143.3 mg).
To a solution of this bis silyl compound (123.4 mg, 0.28 mmol) in 13 ml of
methanol was added 600ul of 30% hydrogen peroxide and 300 ul of 6N sodium
hydroxide. The reaction mixture was stirred at ambient temperature, and an
additional 1 ml of 30% hydrogen peroxide and 375 ul of 6N sodium hydroxide
was added portionwise over a 12 minute period. The reaction was quenched
with saturated solution of ammonium chloride. The aqueous layer was
extracted 3 times with methylene chloride and once with ether. The organic
layer was washed with water, dried over sodium sulfate, and concentrated
in vacuo to provide the 1,8-bis(TBS)-protected title compound (121.8 mg)
in crude form.
Without further purification, the bis silyl epoxide was dissolved in 37 ml
of methylene chloride. To this solution was added 2.5 g of 4A molecular
sieves, and this mixture was stirred at ambient temperature for 10
minutes. Trifluoromethanesulfonic acid (40 ul, 20 ul, 6 ul, -0.76 mmol)
was added portionwise in 5 minute intervals. The reaction mixture was
taken up in methylene chloride and washed with saturated solution of
sodium bicarbonate. The aqueous layer was extracted 3 times with methylene
chloride and once with ether. The organic layer was dried over sodium
sulfate and concentrated in vacuo.
The residue from this reaction was combined with 10 mg. of the same from an
earlier experiment and purified by flash column chromatography on a silica
gel column using ether/pentane as eluant to give the title compound (59.4
mg, 79% overall yield).
IR (KBr): 3434, 2922, 2852, 2196, 1736, 1632, 1246, 1218, 1138, 914, 846
.sup.1 H NMR (CDCl.sub.3): 1.89 (1H, m), 1.98 (1H, m), 2.32 (2H, m), 3.40
)1H, s), 3.74 (1H, s), 3.91 (1H, d), 4.31 (1H, d), 5.96 (2H, s)
.sup.13 C NMR (CDCl.sub.3): .delta.21.056, 25.844, 58.572, 68.515, 73.281,
76.736, 87.940, 93.218, 95.216, 97.393, 123.990, 124.726, 200.073
MS: 231 (M+), 213, 197, 185, 169, 157, 141, 129, 115
EXACT MASS: Calculated for C.sub.13 H.sub.10 O.sub.4 : 231.0657 :
Experimental Value: 231.0653
EXAMPLE 14
1-Hydroxy-bicyclo[7.3.1]trideca-2,6-diyne-4-ene-13-one
##STR33##
(a) (Z)-5-chloro-1-phenoxy-4-pentene-2-yne
To a 1 L flask under Argon was added CuI (7.86 g, 41.2 mmol) and
Pd(PPh.sub.3).sub.4 (5 g, 4.3 mmol). The catalyst was covered with 600 mL
of degassed THF, cis-1,2-dichloroethylene (50 g, 516 mmol), and butylamine
(68 mL, 688 mmol). Phenoxy-2-propyne (45 g, 340 mmol) was added neat over
10 min and the reaction mixture stirred for 5.5 h. Air was bubbled through
the reaction mixture for 15 min and the reaction filtered through a pad of
celite and washed with pentane. The filtrate was washed with water and
brine and the aqueous fractions extracted with ether. The organic
fractions were combined, dried (MgSO.sub.4), filtered through celite and
concentrated. The residue was chromatographed over silica gel (hexane) to
give 44.3 g of a yellow oil (67%).
IR (film) 1598, 1494, 1236, 1214, 1032, 754, 690 cm.sup.-1 ;
.sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta. 7.47 (m, 2H), 6.99 (m, 3H), 6.42
(d, J=7.5 Hz, 1H), 5.90 (dt, J=7.5, 2.0 Hz, 1H), 4.88 (d, J=1.9 Hz, 2H).
.sup.13 C NMR (CDCl.sub.3, 75.5 MHz) .delta. 157.5, 129.5, 129.4, 121.4,
114.9, 111.3, 92.1, 80.9, 56.3;
(b) (Z)-7-phenoxy-1-trimethylsilyl-3-heptene-1,5-diyne
To a 1 L flask under Argon was added CuI (5.24 g, 27 mmol) and
Pd(PPh.sub.3).sub.4 (4.9 g, 4 mmol) and the catalyst covered with 500 mL
of degassed THF. To this solution was added the product of step (a) (42.7
g, 220 mmol) and degassed butylamine (44 mL, 440 mmol). To this solution
was added trimethylsilyl acetylene (29 g, 290 mmol) and the reaction
mixture was stirred for 7 h. Air was bubbled through the solution for 15
min and the reaction mixture filtered through celite and washed with
pentane. The filtrate was washed several times with water and the aqueous
fractions extracted with ether. The organic fractions were combined, dried
(MgSO.sub.4) and concentrated. The residue was chromatographed over silica
gel (hexane) to give 35.1 g of a tan oil (62%).
IR (film) 2144, 1600, 1494, 1250, 1214, 844, 754;
.sup.1 H NMR (CDCl.sub.3, 300 MHz) 7.30 (m, 2H), 7.00 (m, H), 5.87 (s, 2H),
4.89 (s, 2H), 0.21 (s, 9H);
.sup.13 C NMR (CDCl.sub.3, 75.5 MHz) .delta. 157.7, 129.3, 121.3, 120.4,
119.6, 114.8, 103.4, 101.5, 91.8, 84.1, 56.4, -0.31;
(c)
(Z)-6-[[(1,1-dimethylethyl)dimethyl]silyloxy]-6-(7-phenoxy-3-heptene-1,5-d
iynyl)-1-trimethylsilyloxycyclohexene
To a solution of the product of step (b) (5.0 g, 19.7 mmol) in 20 mL THF
was added 5 mL of water and LiOH-H.sub.2 O (5.6 g, 133 mmol). The solution
was stirred for 4 h, diluted with ether and washed with water. The aqueous
layer extracted with ether and then ethyl acetate. The organic fractions
were combined, dried (MgSO.sub.4) and concentrated. The residue was
chromatographed over silica (30:1 hexane/ethyl acetate) to give 3.37 g of
(94%) of 7-phenoxy-3-heptene-1,5-diyne.
This diynene (3.37 g, 18.5 mmol) was dissolved in 60 mL of THF and cooled
to -78 .degree. C. To the cold solution was added LiHMDS (20 mL, 1.0M in
THF, 20 mmol) and stirred 20 min. To this solution was added
2-TBSoxy-2-cyclohexeneone (3.8 g, 16.8 mmol) in 20 mL of THF. The reaction
was immediately brought to 0 .degree. C. and stirred for 30 min.
Trimethylsilyl chloride was added at 0 .degree. C. (3.1 mL, 24.4 mmol) and
stirred for 30 min. The solution was diluted with pentane and washed with
water, dried (MgSO.sub.4), and concentrated. The residue was
chromatographed over silica (200:1 hexane/ethyl acetate) to give 5.22 g of
the desired product (65%) and 627 mg of recovered diynene.
.sup.1 H NMR (CDCl.sub.3, 300 MHz 7.30 (m, 2H), 6.98 (m, 3H), 5.84 (m, 2H),
4.85 (d, J=1.8 Hz, 2H), 4.81 (t, J=4.0 Hz, 1H), 2.02 (m, 4H), 1.68 (m,
2H), 0.89 (s, 9H), 0.22 (s, 12H), 0.19 (s, 3H);
(d)
(Z)-6-[[(1,1-dimethylethyl)dimethyl]silyloxy]-6-(7-phenoxy-3-heptene-1,5-d
iynyl)-1-trimethylsilyloxycyclohexene hexacarbonyl cobalt complex
To a solution of octacarbonyl dicobalt (4.0 g, 11.7 mmol) in 70 mL of
heptane was added the product of step (c) (5.2g, 10.8 mmol) in 30 mL of
heptane. The solution was stirred for 2.5 h, concentrated and the residue
chromatographed over silica gel (98:2 hexane/chloroform) to give 5.88 g of
the desired cobalt complex as the major product (71%) and 1.06 g of the
minor cobalt complexed isomer (13%).
.sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta. 7.28 (m, 2H), 6.98 (m, 3H),
6.67(d, J=10.6 Hz, 1H), 5.83 (d, J=10.6 Hz, 1H), 5.34 (s, 2H), 4.82 (t,
J=4.0 Hz, 1H), 2.01 (m, 4H), 1.75 (m, 1H), 1.56 (m, 1H), 0.87 (s, 9H),
0.17 (s, 12H), 0.14 (s, 3H);
(e)
1-[[(1,1-dimethylethyl)dimethyl]silyloxy]-bicyclo[7.3.1]trideca-2,6-diyne-
4-ene-13-one, hexacarbonyl cobalt complex
To the major cobalt complexed product of step (d) (5.02 g, 6.54 mmol) in
265 mL of dichloromethane at -15 .degree. C. was added ethyl aluminum
dichloride (3.8 mL, 1.8M in toluene, 6.84 mmol). The reaction mixture was
stirred for 30 min and poured into water. The organic fraction was
separated and the aqueous fraction washed with hexane. The organic
fractions were combined, dried (MgSO.sub.4), and concentrated. The residue
was chromatographed over silica gel (30:1 hexane/ethyl acetate) to give
2.64 gm of a burgundy solid (67%).
.sup.1 H NMR (CDCl.sub.3, 300 MHz) 6.97 (d, J=9.8 Hz, 1H), 5.73 (d, J=9.8
Hz, 1H), 4 22 t, J=15 1 Hz, 1H), 3.18 (m, 2H), 2.39 (br d, J=13.0 Hz, 1H),
2.04 (m, 1H), 1.90-1.68 (m, 4H), 0.84 (s, 9H), 0.12 (s, 3H), 0.04 (s, 3H);
(f)
1-[[(1.1-dimethylethyl)dimethyl]silyloxy]-bicyclo[7.3.1]trideca-2,6-diyne-
4-ene-13-one
To the cyclized cobalt complex of step (e) (1.21 g, 2.0 mmol) was added 41
mL of 95% ethanol and ferric nitrate nonahydrate (4.05 g, 10.0 mmol) and
the solution stirred for 3 h. Another equivalent of ferric nitrate was
added (807 mg, 2.0 mmol) and the reaction stirred for an additional 2 h.
The solution was diluted with ether and washed with water and brine. The
organic fraction was dried (MgSO.sub.4) and concentrated. The residue was
chromatographed over silica gel (40:1 hexane/ethyl acetate) to give 541 mg
of a white crystaline solid (86%).
.sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta. 5.85 (s, 2H), 3.20 (dd, J=17.5,
3.0 Hz, 1H), 2.71 (m, 2H), 2.40 (dd, J=17.5, 3.0 Hz, 1H), 2.36 (m, 1H),
2.00 (m, 2H), 1.73 (m, 2H), 0.90 (s, 9H), 0.19 (s, 3H), 0.17 (s, 3H); (g)
1-Hydroxy-bicyclo[7.3.1]trideca-2,6-diyne-4-ene-13-one
A solution of 1.0M tetra-nbutyl ammonium fluoride in THF (0.3375 mL & mmol)
was added to a solution of 96.5 mg (0.3375 mmol) of the product of step
(f) stirring in 5 mL of THF at 25.degree. under an N.sub.2 atmosphere.
After 30 min 50 mL of water was added and the mixture was extracted with
three 25 mL portions of diethyl ether. The combined organic extracts were
washed with saturated aqueous brine and dried over sodium sulfate. Flash
chromatography (twice) over silica gel using 20% EtOAc/hexane provided 44
mg (72%) of the title compound as a white solid:
IR (NaCl) 3466, 2200, 1718, 1456, 1424 cm.sup.-1.
.sup.1 H NMR (CDCl.sub.3) .delta. 5.82 (s,2H), 4.04 (bs, --OH), 3.19 (dd,
J=17.6,2.44Hz,1H), 2.85-2.70 (m,2H), 2.51-2.41 (m,2H), 2.05-1.85 (m,2H),
1.78-1.65 (m,2H).
.sup.13 C NMR (CDCl.sub.3) .delta. 207.17, 125.33, 122.19, 99.98, 97.42,
90.32, 84.14, 72.11, 47.75, 33.73, 24.11, 24.02, 18.40.
EXAMPLE 15
1-Hydroxy-bicylco[7.3.1]trideca-4,9-diene-2,6-diyne-13-one
##STR34##
(a)
1-[[(1,1-dimethyethyl)dimethyl]silyloxy]bicyclo[7.3.1]trideca-4,9-diene-2,
6-diyne-13-one
To the product of Example 14 (593 mg, 1.88 mmol) in 40 mL of THF at -78
.degree. C. was added KHMDS (4.7 mL, 0.5M in toluene, 2.35 mmol) and
stirred 20 min. 2,2'-Dipyridyl disulfide (515 mg, 2.34 mmol) in 2 mL of
THF was added to the deeply colored enolate. The reaction was held at
-78.degree. C. for 30 min and then poured into water and diluted with
ether. The organic fraction was dried (MgSO.sub.4), concentrated and
chromatographed over silica (20:1 hexane/ethyl acetate) to give 583 mg of
9-(2-pyridylthio)-substituted starting material (73%) which was
immediately oxidized.
This sulfide (585 mg, 1.376 mmol) was dissolved in 27 mL dichloromethane
and cooled to 0 .degree. C. To the cold solution was added mCpBA (453 mg,
55%, 1.44 mmol) and the solution was stirred for 30 min. The cold bath was
removed and the solution stirred at room temperature for 4 h. The solution
was diluted with chloroform and washed with sat. bicarbonate, dried
(MgSO.sub.4), and concentrated. The residue was chromatographed over
silica gel (30:1 hexane/ethyl acetate) to give 412 mg of the desired
product as a white solid (70%).
.sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta. 6.34 (br t, J=3.0 Hz, 1H), 5.81
(s, 2H), 3.66 (d, J =16.7 Hz, 1H), 2.99 (d, J=16.7 Hz, 1H), 2.48 (m, 2H),
2.29 (m, 1H), 2.14 (m, 1H), 0.92 (s, 9H), 0.21 (s, 3H), 0.17 (s, 3H);
(b) 1-Hydroxy-bicylco[7.3.1]trideca-4,9-diene-2,6-diyne-13-one
To the product of step (a) (73 mg, 0.234 mmol) was added 10.5 mL of
acetonitrile and 1.8 mL of 48% HF and the solution was stirred in a
plastic reactor for 18 h. The solution was diluted with chloroform and
washed with water. The aqueous fraction was extracted with chloroform and
the organic fractions combined, dried (K.sub.2 CO.sub.3), and
concentrated. The residue was chromatographed over silica gel (5:1
hexane/ethyl acetate) to give 44 mg of the title compound as a white solid
(96%).
IR(KBr) 3468, 2186 (W), 1692, 1640, 1364, 1340, 1128, 1108, 1046, 964
cm.sup.-1 ;
.sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta. 6.48 (m, 1H), 5.79 (s, 2H), 4.08
(s, 1H), 3.77 (d, J=16.7 Hz, 1H), 3.04 (d, J=16.7 Hz, 1H), 2.51 (m, 2H),
2.45 (m, 1H), 2.06 (m, 1H);
.sup.13 C NMR (CDCl.sub.3, 75.5 MHz) .delta. 192.8, 141.2, 135.4, 124.4,
121.2, 99.9, 95.5, 90.6, 87.4, 72.0, 32.0, 24.8, 23.9;
MS (DCI) m/z 199 MH.sup.+, 181 MH.sup.+ --OH), 153 (MH.sup.+ --CO);
EXAMPLE 16
1,11-Dihydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyne-13-one
##STR35##
(a)
1-[[(1,1-dimethylethyl)dimethyl]silyloxy]-11-hydroxy-bicyclo-[7.3.1]tridec
a-4,9-diene-2,6-diyne-13-one and
1-[[(1,1-dimethylethyl)dimethyl]silyloxy]-bicyclo[7.3.1]-trideca-4,9-diene
-2,6-diyne-11,13-dione
To the product of Example 15, step (a) (142 mg, 0.45 mmol) in 25 mL dioxane
was added selenium dioxide (164 mg, 1.47 mmol) and the solution heated to
90 .degree. C. for 5 h. The solution was diluted with chloroform and
washed with bicarbonate. The aqueous fraction was extracted with
chloroform and the organic fractions combined and dried (MgSO.sub.4). The
solution was concentrated and the residue chromatographed over silica gel
(3:1 hexane/ethyl acetate) to give 82 mg of allylic alcohol (55%), 6 mg of
dione (4%) and 20 mg of recovered starting enone (14%).
enone:
IR (film) 3424, 2956, 2930, 2856, 2194 (w), 1716, 1256, 1162, 1040, 1014,
976, 834, 782 cm.sup.-1 ;
.sup.1 H NMR (CDCl.sub.3, 300 MHz) 6.38 (t, J=2.5 Hz, 1H), 5.82 (ABq, 2H),
4.55 (m, 1H), 3.73 (d, J=16.6 Hz, 1H), 3.04 (d, J=16.6 Hz, 1H), 2.80 (ddd,
J=12.9, 6.1, 20 Hz, 1H), 2.08 (dd, J=12.9, 9.6 Hz, 1H), 0.92 (s, 9H), 0.21
(s, 3H), 0.18 (s, 3H);
MS (DCI) m/z 329 (MH.sup.+), 311(MH.sup.+ --OH), 271(MH.sup.+ --tBu),
197(MH.sup.+ --OSiMe.sub.2 tBu)
dione:
.sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta. 6.39 (s, 1H), 5.86 (s, 2H), 3.84
(d, J=16.1 Hz, 1H), 3.25 (dd, J=17.4, 1.7 Hz, 1H), 3.21 (d, J=16.1 Hz,
1H), 2.95 (d, J=17.4 Hz, 1H), 0.91 (s, 9H), 0.20 (s, 3H), 0.17 (s, 3H);
(b) 1,11-Dihydroxy-bicyclo[7 3.1]trideca-4,9-diene-2,6-diyne-13-one
To the protected allylic alcohol of step (a) (88 mg, 0.268 mmol) was added
8.5 mL of acetonitrile and 2.5 mL of 48% HF and the reaction stirred 30 h.
The solution was diluted with chloroform and washed with water. The
aqueous fraction was extracted with chloroform and the organic fractions
combined and dried over K.sub.2 CO.sub.3. The solution was concentrated
and chromatographed over silica (1:1 hexane/ ethyl acetate) to give 58 mg
of the title compound as a white solid (quantitative).
IR (KBr) 3388, 2188 (w), 1706, 1156, 1038 cm.sup.-1 ;
.sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta. 6.50 (t, J=2.5 Hz, 1H), 5.80
(ABq, 2H), 4.60 (m, 1H), 4.04 (br s, 1H), 3.70 (d, J=16.6 Hz, 1H), 3.08
(d, J=16.6 Hz, 1H), 2.91 (d ABq, 1H), 2.02 (ABq, 1H);
.sup.13 C NMR (DMSO, 75.5 MHz) .delta. 194.1, 144.4, 136.5, 125.6, 122.6,
101.3, 97.6, 91.2, 88.9, 74.0, 67.2, 44.0, 24.9;
EXAMPLE 17
1-Hydroxy-bicyclo[7.3.1)trideca-4,9-diene-2,6-diyne- 11,13-dione.
##STR36##
The silyl protected dione obtained in Example 16, step (a) was dissolved in
4.25 mL of acetonitrile and stirred with 0.75 mL of 48% HF for 24 h. The
solution was diluted with chloroform and washed with water. The organic
fraction was dried over K.sub.2 CO.sub.3, concentrated and the residue
chromatographed over silica gel (3:1 hexane/ethyl acetate) to yield 4.5 mg
of the deprotected dione (88%).
.sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta. 6.48 (s, 1H), 5.87 (s, 2H), 3.92
(s, 1H), 3.88 (d, J=16.3 Hz, 1H), 3.42 (d, J=17.6 Hz, 1H), 3.26 (d J=16.3
Hz, 1H), 2.94 (d, J=17.6 Hz, 1H);
EXAMPLE 18
1,8-Dihydroxy-bicyclo[7.3.1]trideca-4-ene-2,6-diyne-13-one
##STR37##
Bromine (0.341 mL) was added dropwise to a solution of 1.5 g (6.62mmol) of
2-(t-butyldimethylsilyloxy)-2-cyclohexenone stirring in 100 mL of CH.sub.2
Cl.sub.2 at 25.degree. under an atmosphere of nitrogen. The color of the
the bromine was nearly completely discharged after addition was complete.
After 5 min 2.2 mL of triethylamine was added and the reaction was stirred
for 2.5 h. The reaction was poured into 50 mL of water and extracted. The
aqueous layer was reextracted with 10 mL of CH.sub.2 Cl.sub.2 and the
combined organic extracts were dried over anhydrous sodium sulfate.
Concentration in vacuo provided a tan solid which was purified by flash
chromatography over silica gel using 3-5% ethyl acetate in hexane as
eluent. Concentration of the product fractions in vacuo provided 1.85g
(91%) of white crystalline solid which was the desired
3-bromo-2-TBSoxy-2-cyclohexenone. Spectroscopy showed this material to be
about 95% pure and to contain about 5% of the starting enone.
A 1.0M solution of lithium bistrimethylsilylamide in tetrahydrofuran
(5.7mL) was added to a solution of 0.97g (5.44mmol) of
(Z)-1-lithio-7,7-diethoxy-3-heptene-1,5-diyne in 54 mL of THF stirring at
-78.degree.. A solution of the bromide prepared as above (1.58 g, 5.18
mmol) in 10 mL of THF at -78.degree. was added via cannula over 1 min. The
cooling baths were removed and the reaction allowed to stir at ambient
temperature (25.degree. ) for 1.25h. The reaction was poured into 200 mL
of water and extracted with 300 mL of 3:1 diethyl ether/ ethyl acetate.
The aqueous layer was reextracted with 100 mL of diethyl ether and then
the combined organic extracts were washed with 100 mL of saturated brine.
The extracts were dried over sodium sulfate, filtered, and concentrated in
vacuo to provide 2.22 g of brown syrup which by 1H NMR was amixture of a
major and minor bromoketone
(Z)-2-bromo-6-TBSoxy-6-(7,7-diethoxy-3-heptene-1,5-diynyl)cyclohexanone.
This crude material was used directly in the cobalt complexation step.
Octacarbonyl dicobalt (0.17 g) was added to a solution of 0.241 g of the
bromoketones in 15 mL of CH.sub.2 Cl.sub.2 stirring at 25.degree. under an
N.sub.2 atmosphere. The reaction was stirred for 1 h, concentrated in
vacuo, and purified by flash chromatography. Isolation of only the major
product provided 166 mg of a dark reddish purple oil which was a single
compound and the desired cobalt complex of
(Z)-2-bromo-6-TBSoxy-6-(7,7-diethoxy-3-heptene-1,5-diynyl)cyclohexanone.
Titanium tetrachloride (71 ul) was added in one portion to a solution of
the above cobalt complexed
(Z)-2-bromo-6-TBSoxy-6-(7,7-diethoxy-3-heptene-1,5-diynyl)cyclohexanone
(166 mg) and DABCO (25 mg) in 15 mL CH.sub.2 Cl.sub.2 stirring at
-78.degree. under an atmosphere of nitrogen. The reaction was stirred for
5 minutes and then poured into water. The reaction was extracted and dried
over sodium sulfate. Filtration, concentration, and purification by flash
chromatography over silica gel using 5% ethyl acetate in hexane provided
121 mg of the desired cobalt complexed
(Z)-2-bromo-6-TBSoxy-6-(7-oxo-3-heptene-1,5-diynyl)cyclohexanone as a
purple oil.
Activated granular zinc (19 mg) was added to a solution of 0.2 mL 1.0M
Et-.sub.2 AlCl in hexanes, 2.0 mL Ti(OiPr).sub.4, 2 mg CuBr, and 0.121 g
of cobalt complexed
(Z)-2-bromo-6-TBSoxy-6-(7-oxo-3-heptene-1,5-diynyl)cyclohexanone stirring
at 2.degree. in 4.5 mL of dry THF. The reaction was allowed to warm to
10.degree. over 20 min and then was allowed to stir for 60 min during
which time the temperature was maintained between 10.degree. and
20.degree.. The reaction was poured into 40 mL of 1N HCl and 50 mL diethyl
ether and extracted. The aqueous layer was reextracted with an additional
10 mL of diethyl ether and the combined organic extracts were dried over
sodium sulfate. Filtration, concentration in vacuo, and purification by
flash chromatography on silica gel using 5% then 10% ethyl acetate in
hexane as eluent provided 35 mg of reddish purple oil which was the
desired cobalt complexed
8-hydroxy-1-TBSoxy-bicyclo[7.3.1]trideca-4-ene-2,6-diyne13-one.
Solid Fe(NO.sub.3).sub.3.9H.sub.2 O (0.48 g) was added in one portion to a
solution of 0.24 g cobalt complexed
8-hydroxy-1-TBSoxy-bicyclo[7.3.1]trideca-4-ene-2,6-diyne-13-onestirring in
45 mL of CH.sub.2 Cl.sub.2 at 25.degree.. The reaction was stirred for 3 h
and then an additional 155 mL of CH.sub.2 Cl.sub.2 and 0.66 g ferric
nitrate was added. The reaction was stirred for 40 min and then an
additional 0.71 g of ferric nitrate was added. The reaction was stirred
for 1 h and then 200 mL of water was added. The reaction was extracted and
the aqueous layer was rextracted With 200mL of diethyl ether. The combined
organic extracts were washed with saturated brine and then dried over
sodium sulfate. Flash chromatography over silica gel using 3% then 5%
ethyl acetate in hexane as eluent provided 72 mg of the desired
8-hydroxy-1-TBSoxy-bicyclo[7.3.1] trideca-4-ene-2,6-diyne-13-one as an
offwhite solid.
Trifluoromethane sulfonic acid (16 ul) was added in one portion to a
solution of 65 mg
8-hydroxy-1-TBSoxybicyclo[7.3.1]trideca-4-ene-2,6-diyne-13-one in 20 mL of
CH.sub.2 Cl.sub.2 stirring over 1 g of 2A molecular sieves at 25.degree..
The reaction was stirred for 10min and then poured into 10 %aq NaHCO.sub.3
and CH.sub.2 Cl.sub.2. The mixture was extracted and the organic extracts
were dried over sodium sulfate. Filtration, concentration, and
purification by flash chromotography over silica gel using 1:1 diethyl
ether/hexane as eluent provided 26mg of the desired
1,8-dihydroxy-bicyclo[7.3.1]trideca-4-ene-2,6-diyne-13-one:
.sup.1 H NMR (CDCl.sub.3) 5.90 (s, 2H), 4.57 (m,1H), 3.95 (m, 1H) 3.83
(s,1H), 2.98 (m, 1H), 2.45 (m, 2H), 2.20-1.60 (m, 4H).
##STR38##
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